醛固酮腺瘤模型大鼠主动脉损伤机制的实验研究
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摘要
背景
继发性高血压的最常见原因是原发性醛固酮增多症(Primary aldosteronism, PA),肾上腺醛固酮腺瘤(Aldosterone-producing adenoma, APA)是PA的主要类型。APA的主要治疗方法是腺瘤切除或者患侧肾上腺全切。然而,即使手术,仍有部分患者术后效果不佳,具体机制还未阐明。
传统认为,醛固酮在肾上腺皮质球状带合成,通过肾脏引起水钠潴留导致高血压。最近发现,血管也能合成醛固酮,并表达盐皮质激素受体(MR)和11-β-羟基类固醇脱氢酶2(11-β-hydroxysteroid dehydrogenase2,11-β-HSD2)。所以,醛固酮可以直接作用于血管导致血管损伤。研究表明醛固酮可以引起血管氧化应激、炎症和纤维化等。
体外实验证实,醛固酮可以刺激血管平滑肌细胞(Vascular smooth muscle cell, VSMC)增殖。Nakamura等报道,在细胞水平,醛固酮可以诱导人主动脉平滑肌细胞MDM2表达。MDM2是一种核蛋白,能够与p53形成复合体,阻止p53介导的细胞凋亡或逆转p53引起的G1期和G2期停滞,促进增殖,抑制其表达后,醛固酮的促VSMC增殖的能力也被抑制。我们前期研究发现,醛固酮灌注的大鼠主动脉MDM2表达增加。然而,在动物水平,醛固酮是否能够诱导主动脉平滑肌细胞增殖及MDM2和p53在其中的作用还需要进一步阐明。
除了增殖,最近报道醛固酮还能够诱导多种细胞凋亡。醋酸脱氧皮质酮是另一种盐皮质激素,醋酸脱氧皮质酮-盐大鼠的主动脉内凋亡细胞增加。与正常大鼠相比,转基因Ren2大鼠血浆醛固酮和血管紧张素Ⅱ浓度升高,并且主动脉内凋亡细胞也增多。但是醛固酮单独是否能够诱导主动脉细胞凋亡还未被证实。
此外,醛固酮还能够促进细胞外基质沉积。Fibulin家族蛋白是一类细胞外基质蛋白,fibulin-5是fibulin家族的新成员,它在弹力纤维的形成过程中是必不可少的。Fibulin-5表达异常与皮肤松弛症、肺气肿及年龄相关性黄斑退变等疾病密切相关。特发性门静脉高压患者的门静脉大分支fibulin-5表达增加。与之相反,胸主动脉夹层动脉瘤患者主动脉fibulin-5表达减少。相对于野生型细胞,来源于fibulin-5-/-小鼠的VSMC在丝裂原刺激下增殖和迁移能力增加,过表达fibulin-5可以抑制这种现象。研究还发现fibulin-5 mRNA在多种恶性肿瘤中表达缺失,提示fibulin-5在这些肿瘤中可能起抑癌的作用。所以,fibulin-5是一种多功能蛋白。最近发现,fibulin-5是TGF-β1新的靶基因,TGF-β1能够以剂量和时间依赖的方式诱导fibulin-5在成纤维细胞和内皮细胞内表达。
综上所述,研究醛固酮对主动脉平滑肌细胞增殖、凋亡和细胞外基质蛋白fibulin-5的作用是十分重要的,能够帮助我们揭示PA的致病机理和APA术后高血压的原因。
本课题通过建立APA大鼠模型,检测主动脉细胞增殖和凋亡的状态及相关基因的表达,最后检测主动脉fibulin-5含量和TGF-β1的表达。相较于传统上的非特异性MR拮抗剂螺内酯,依普利酮是一种特异性MR拮抗剂,能增强与MR结合的特异性,减少螺内酯引起的并发症。肼苯哒嗪是外周血管扩张剂,对主动脉影响很小。在本课题中我们还应用依普利酮和肼苯哒嗪干预醛固酮的作用,探讨醛固酮引起血管损伤的发生机制。
方法
1.32只SD大鼠随机分为4组,每组8只：①空白溶剂设为对照组(60%丙二醇+10%乙醇+30%双蒸水)；②APA组,泵入醛固酮(1μg／h)；③APA+特异性MR阻断剂组,依普利酮(100mg/kg/d);④APA+血管扩张剂组,肼苯哒嗪(25mg/kg/d)。根据分组情况,在ALZET 2004微量渗透泵储药仓内分别注入醛固酮溶液或空白溶剂,然后将泵埋植于大鼠皮下。ALZET 2004微量渗透泵可以持续工作4周,为使醛固酮作用时间达到8周,4周后更换渗透泵。依普利酮和肼苯哒嗪溶于饮用水中,每日灌胃一次。每周测量大鼠尾动脉收缩压一次。8周后,放免法检测血浆醛固酮浓度和肾素活性并测量大鼠主动脉中膜厚度和横截面面积。
2.免疫组化和Western印迹法检测主动脉增殖细胞核抗原(proliferating cell nuclear antigen, PCNA)阳性的VSMC数及PCNA的表达水平。随后通过免疫组化、RT-PCR和Western印迹检测MDM2和p53的表达水平。
3.通过TUNEL法检测大鼠主动脉细胞凋亡。Western印迹法检测细胞色素c和caspase-3的含量。免疫组织化学和Western印迹法检测Bcl-2和Bax的表达水平。
4.免疫组化和Western印迹法检测主动脉fibulin-5及TGF-β1的表达水平。
结果
1.与对照组相比,三周后APA组大鼠收缩压开始升高,第7周达到顶峰,之后维持在高水平(P<0.05)。服用依普利酮或肼苯哒嗪后,APA大鼠收缩压显著下降,但并不能降至对照组的水平(P<0.05)。泵入醛固酮,无论是否给予依普利酮或肼苯哒嗪,大鼠血浆醛固酮的浓度都明显升高(p<0.01),肾素活性则被显著抑制(p<0.01)。除对照组外其它三组大鼠醛固酮浓度和肾素活性没有显著差异。与对照组相比,APA组主动脉横截面面积和主动脉中膜厚度有增加的趋势,但是差异没有统计学意义(P=0.108；P=-0.068)。
2.与对照组大鼠相比,免疫组化结果显示APA大鼠主动脉PCNA阳性VSMC显著增多(P<0.01),Western印迹进一步证实APA大鼠主动脉PCNA表达更多。MDM2在mRNA和蛋白水平表达都上调(P<0.05)；而p53只在蛋白水平表达增加(P<0.05)。
3.相较于对照组大鼠,APA大鼠主动脉显示TUNEL阳性细胞显著增多(P<0.05),有细胞色素C和活化的caspase-3增加(P<0.05)；Bax表达上调(P<0.05),Bcl-2表达下降(P<0.05)。
4.APA大鼠主动脉与对照组相比,fibulin-5和TGF-β1表达均显著增加(P<0.01)。
5.醛固酮的上述作用能够被依普利酮抑制,但不被肼苯哒嗪抑制。
结论
1.通过在大鼠皮下埋植的微量渗透泵持续灌注醛固酮能够模拟APA的激素释放方式,建立APA模型,为研究APA的致病机理提供了很好的平台。
2.在体内,醛固酮通过诱导MDM2表达,逆转p53对细胞周期的阻滞作用,促进VSMC增殖。
3.醛固酮通过线粒体途径诱导平滑肌细胞和内皮细胞凋亡。
4.醛固酮促使主动脉fibulin-5沉积增加,后者至少部分是通过醛固酮诱导的TGF-β1引起的。
5.醛固酮的上述作用是醛固酮与MR结合后对主动脉的直接作用,与醛固酮的血压升高效应无关。
Background
Primary aldosteronism (PA), mainly deriving from adrenal aldosterone-producing adenoma (APA), is the most common cause of secondary hypertension. However, even after the resection of adenomas, a part of patients still suffer from hypertension, which is possibly due to irreversible vascular remodeling. Aldosterone is traditionally believed to be produced in the adrenal cortex and elevates BP through renal effects on sodium and water retention via binding to the mineralocorticoid receptor (MR). However, it was recently reported that blood vessels per se produced aldosterone and synthesized MRs and 11-β-hydroxysteroid-dehydrogenase-2, an essential enzyme for aldosterone specifically binding to MRs. Thus, blood vessels possess a complete system for aldosterone activity. a lot of studies have shown that aldosterne induces vascular oxidative stress, inflammation and fibrosis, resulting in vascular damage and remodeling.
In in vitro studies, aldsoterone was shown to stimulate vascular smooth muscle cell (VSMC) proliferation. MDM2, a mediator that promotes cell proliferation mainly by forming a complex with p53 and inhibiting p53-mediated G1 and G2 cell cycle arrest and apoptosis. Recently, Nakamura et al. reported that aldosterone induced MDM2 expression in aortic smooth muscel cells by mineralocorticoid receptors. Moreover, after suppressing MDM2 expression, the effect of aldosterone on VSMC proliferation was also inhibited. Our previous study showed that aldosterone induced MDM2 expression in the aorta in vivo. However, whether aldosterone induces VSMC proliferation in vivo as well as the roles of MDM2 and p53 in the proliferation effect of aldosterone need to be elucidated.
In addition to VSMC proliferation, previous studies have shown that aldsoterone induces vascular oxidative stress, inflammation and fibrosis, resulting in vascular damage and remodeling. Recently, aldosterone was demonstrated to induce the apoptosis of several types of cells. In addition, deoxycorticosterone acetate (DOCA)-salt rats, another animal model of excessive mineralocorticoid, presented with increased apoptotic vascular smooth muscle cells (VSMCs) in the aorta. Moreover, transgenic Ren2 rats with elevated plasma aldosterone concentration and angiotensin II activity exhibited more apoptotic vascular cells in the aorta than normal rats. Nevertheless, whether aldosterone stimulates aortic apoptosis in vivo is unknown.
Besides, aldosterone also promotes extracellular matrix (ECM) deposition. Fibulin-5, a secreted (ECM) glycoprotein, is the new member of fibulin family. Recent studies have identified fibulin-5 as an essential protein for elastic fiber assembly. Inactivation of the fibulin-5 gene in mice results in a generalized elastinaopathy affecting those organs with abundant elastic fibers including blood vessels. Fibulin-5 was shown to be involved in phlebosclerosis of major portal vein branches associated with elastic fiber deposition in idiopathic portal hypertension. In contrast, decreased expression of fibulin-5 correlating with reduced elastin in thoracic aortic dissection was found. Compared with wild type cells, VSMCs from fibulin-5-/- mices demonstrated more proliferation and migration under the stimulation of mitogen, which could be inhibited after overexpression of fibulin-5, suggesting that fibulin-5 is a suppressor of proliferation and migration. Studies demonstrated the lack of fibulin-5 mRNA in most malignant tumors, implying that fubulin-5 acts as a suppressor in most cancers. Therefore, fibulin-5 is a multfunctional protein. Fibulin-5 was reported to be a new target gene of TGF-β1 that induces fibulin-5 expression in fibroblasts and endothelial cells.
In the current study, we first constructed rat models of APAs by subcutaneously implanting osmotic mini-pumps in rats. After 8 week infusion of aldosterone, aortic morphology was observed. Then we examined the status of aortic proliferation and apoptosis as well as the expressions of proliferation and apoptosis-related genes. Finally, we evaluated the effects of aldosterone on fibulin-5 deposition and TGF-β1 expression in the aorta. Relative to spironolactone, eplerenone is a specific mineralocorticoid receptor (MR) blocker, which can enhance the selectivity of binding MRs and reduce the side effects by spironolactone. Hydralazine is an old drug used for the treatment of hypertension by directly dilating the resistance arteries with minor effects on aortas. In the present study, we take use of the two drugs to interfere the effect of aldosteone on the aorta to explore the mechanisms of aortic damage by aldosterone.
Methods
1.32 Sprague-Dawley rats, each subcutaneously implanted with an osmotic mini-pump, were randomly divided into 4 groups:vehicle as control; aldosterone (1μg/h); aldosterone plus eplerenone (100 mg/kg/day) and aldosterone plus hydralazine (25 mg/kg/day). Because Alzet 2004 minipump continuously infuses the test substances only for 4 weeks, another minipump was implanted after the fourth week to realize the goal of 8 week effect of aldosterone on rats. Eplerenone and hydralazine were dissolved in drinking water. Systolic blood pressure (SBP) was measured weekly by the tail-cuff method. At the termination of the study, blood was collected for measurements of plasma renin activity (PRA) and aldosterone concontration (PAC) with radioimmunoassay kits. Then, media width (MW) and cross sectional area (MCSA) of the aortas were measured.
2. After 8 weeks, the PCNA-positive VSMCs and PCNA expression level in the aorta were examined by immunohistochemistry and Western blotting. In addition, the expressions of MDM2 and p53 genes were examined by immunohistochemistry, RT-PCR and Western blotting.
3. Apoptosis was examined by TUNEL assay. The levels of cytochrome c and caspase-3 were determined by Western blotting and the expressions of Bax and Bcl-2 were evaluated by immnuohistochemistry and Western blotting.
4. The expressions of fibulin-5 and TGF-β1 were examined by immnuohistochemistry and Western blotting.
Results
1. Rat models of APAs were successfully established. SBP was similar among the groups at the beginning of the experiment. After 3 weeks, aldosterone-infused rats showed significantly and progressively increased SBP compared with controls (P<0.05). The increase was significantly but incompletely inhibited after treatment with eplerenone or hydralazine (P<0.05). As expected, PAC was significantly increased with significantly depressed PRA in APA rats; and both were unaffected by eplerenone or hydralazine.
2. The MW and MCSA of the aorta in APA rats had a trend to increase relative to those of control rats. However, the increase did not achieve statistical significance(P=0.108; P=0.068, respectively).
3. Compared with controls, APA rats showed more PCNA-positive cells and higher PCNA expression (p<0.01). Upregulated expressions of both MDM2 mRNA and protein were shown in the aorta, associated with elevated p53 protien (P<0.05).4. Compared with controls, APA rats exhibited elevated aortic vascular cell apoptosis accompanied with higher levels of cytochrome c and activated caspase-3 as well as significantly upregulated Bax and downregulated Bcl-2.
4. Relative to control rats, APA rats exhibited increases in fibulin-5 deposition and TGF-β1 expression.
5. All the above effects of aldosterone on the aorta were significantly inhibited after co-administration with eplerenone but not with hydralazine.
Conclusions
1. By subcutaneously implanting osmotic minipumps in rats, the rat models of APAs can be successfully established, providing a good platform for investigating the pathogenesis of APAs.
2. Aldosterone promotes aortic VSMC proliferation, which contributes to aldosterone-induced vascular remodeling, at least partially by upregulating the expression of MDM2 that is able to inhibit the effect of cell cylcle arrest of simultaneously elevated p53.
3. Aldosterone induces vascular cell apoptosis in vivo, which may contribute to aldosterone-mediated aortic injury.
4. Aldosterone directly promotes aortic deposition of fibulin-5 that is at least partially stimulated by aldsoterone-induced TGF-β1.
5. All the above effects of aldosterone on the aorta are the direct effects of aldosterone via MRs and independently of the aldosterone-mediated increase of blood pressure.
继发性高血压的最常见原因是原发性醛固酮增多症(Primary aldosteronism, PA),肾上腺醛固酮腺瘤(Aldosterone-producing adenoma, APA)是PA的主要类型。APA的主要治疗方法是腺瘤切除或者患侧肾上腺全切。然而,即使手术,仍有部分患者术后效果不佳,具体机制还未阐明。
传统认为,醛固酮在肾上腺皮质球状带合成,通过肾脏引起水钠潴留导致高血压。最近发现,血管也能合成醛固酮,并表达盐皮质激素受体(MR)和11-β-羟基类固醇脱氢酶2(11-β-hydroxysteroid dehydrogenase2,11-β-HSD2)。所以,醛固酮可以直接作用于血管导致血管损伤。研究表明醛固酮可以引起血管氧化应激、炎症和纤维化等。
体外实验证实,醛固酮可以刺激血管平滑肌细胞(Vascular smooth muscle cell, VSMC)增殖。Nakamura等报道,在细胞水平,醛固酮可以诱导人主动脉平滑肌细胞MDM2表达。MDM2是一种核蛋白,能够与p53形成复合体,阻止p53介导的细胞凋亡或逆转p53引起的G1期和G2期停滞,促进增殖,抑制其表达后,醛固酮的促VSMC增殖的能力也被抑制。我们前期研究发现,醛固酮灌注的大鼠主动脉MDM2表达增加。然而,在动物水平,醛固酮是否能够诱导主动脉平滑肌细胞增殖及MDM2和p53在其中的作用还需要进一步阐明。
除了增殖,最近报道醛固酮还能够诱导多种细胞凋亡。醋酸脱氧皮质酮是另一种盐皮质激素,醋酸脱氧皮质酮-盐大鼠的主动脉内凋亡细胞增加。与正常大鼠相比,转基因Ren2大鼠血浆醛固酮和血管紧张素Ⅱ浓度升高,并且主动脉内凋亡细胞也增多。但是醛固酮单独是否能够诱导主动脉细胞凋亡还未被证实。
此外,醛固酮还能够促进细胞外基质沉积。Fibulin家族蛋白是一类细胞外基质蛋白,fibulin-5是fibulin家族的新成员,它在弹力纤维的形成过程中是必不可少的。Fibulin-5表达异常与皮肤松弛症、肺气肿及年龄相关性黄斑退变等疾病密切相关。特发性门静脉高压患者的门静脉大分支fibulin-5表达增加。与之相反,胸主动脉夹层动脉瘤患者主动脉fibulin-5表达减少。相对于野生型细胞,来源于fibulin-5-/-小鼠的VSMC在丝裂原刺激下增殖和迁移能力增加,过表达fibulin-5可以抑制这种现象。研究还发现fibulin-5 mRNA在多种恶性肿瘤中表达缺失,提示fibulin-5在这些肿瘤中可能起抑癌的作用。所以,fibulin-5是一种多功能蛋白。最近发现,fibulin-5是TGF-β1新的靶基因,TGF-β1能够以剂量和时间依赖的方式诱导fibulin-5在成纤维细胞和内皮细胞内表达。
综上所述,研究醛固酮对主动脉平滑肌细胞增殖、凋亡和细胞外基质蛋白fibulin-5的作用是十分重要的,能够帮助我们揭示PA的致病机理和APA术后高血压的原因。
本课题通过建立APA大鼠模型,检测主动脉细胞增殖和凋亡的状态及相关基因的表达,最后检测主动脉fibulin-5含量和TGF-β1的表达。相较于传统上的非特异性MR拮抗剂螺内酯,依普利酮是一种特异性MR拮抗剂,能增强与MR结合的特异性,减少螺内酯引起的并发症。肼苯哒嗪是外周血管扩张剂,对主动脉影响很小。在本课题中我们还应用依普利酮和肼苯哒嗪干预醛固酮的作用,探讨醛固酮引起血管损伤的发生机制。
方法
1.32只SD大鼠随机分为4组,每组8只：①空白溶剂设为对照组(60%丙二醇+10%乙醇+30%双蒸水)；②APA组,泵入醛固酮(1μg／h)；③APA+特异性MR阻断剂组,依普利酮(100mg/kg/d);④APA+血管扩张剂组,肼苯哒嗪(25mg/kg/d)。根据分组情况,在ALZET 2004微量渗透泵储药仓内分别注入醛固酮溶液或空白溶剂,然后将泵埋植于大鼠皮下。ALZET 2004微量渗透泵可以持续工作4周,为使醛固酮作用时间达到8周,4周后更换渗透泵。依普利酮和肼苯哒嗪溶于饮用水中,每日灌胃一次。每周测量大鼠尾动脉收缩压一次。8周后,放免法检测血浆醛固酮浓度和肾素活性并测量大鼠主动脉中膜厚度和横截面面积。
2.免疫组化和Western印迹法检测主动脉增殖细胞核抗原(proliferating cell nuclear antigen, PCNA)阳性的VSMC数及PCNA的表达水平。随后通过免疫组化、RT-PCR和Western印迹检测MDM2和p53的表达水平。
3.通过TUNEL法检测大鼠主动脉细胞凋亡。Western印迹法检测细胞色素c和caspase-3的含量。免疫组织化学和Western印迹法检测Bcl-2和Bax的表达水平。
4.免疫组化和Western印迹法检测主动脉fibulin-5及TGF-β1的表达水平。
结果
1.与对照组相比,三周后APA组大鼠收缩压开始升高,第7周达到顶峰,之后维持在高水平(P<0.05)。服用依普利酮或肼苯哒嗪后,APA大鼠收缩压显著下降,但并不能降至对照组的水平(P<0.05)。泵入醛固酮,无论是否给予依普利酮或肼苯哒嗪,大鼠血浆醛固酮的浓度都明显升高(p<0.01),肾素活性则被显著抑制(p<0.01)。除对照组外其它三组大鼠醛固酮浓度和肾素活性没有显著差异。与对照组相比,APA组主动脉横截面面积和主动脉中膜厚度有增加的趋势,但是差异没有统计学意义(P=0.108；P=-0.068)。
2.与对照组大鼠相比,免疫组化结果显示APA大鼠主动脉PCNA阳性VSMC显著增多(P<0.01),Western印迹进一步证实APA大鼠主动脉PCNA表达更多。MDM2在mRNA和蛋白水平表达都上调(P<0.05)；而p53只在蛋白水平表达增加(P<0.05)。
3.相较于对照组大鼠,APA大鼠主动脉显示TUNEL阳性细胞显著增多(P<0.05),有细胞色素C和活化的caspase-3增加(P<0.05)；Bax表达上调(P<0.05),Bcl-2表达下降(P<0.05)。
4.APA大鼠主动脉与对照组相比,fibulin-5和TGF-β1表达均显著增加(P<0.01)。
5.醛固酮的上述作用能够被依普利酮抑制,但不被肼苯哒嗪抑制。
结论
1.通过在大鼠皮下埋植的微量渗透泵持续灌注醛固酮能够模拟APA的激素释放方式,建立APA模型,为研究APA的致病机理提供了很好的平台。
2.在体内,醛固酮通过诱导MDM2表达,逆转p53对细胞周期的阻滞作用,促进VSMC增殖。
3.醛固酮通过线粒体途径诱导平滑肌细胞和内皮细胞凋亡。
4.醛固酮促使主动脉fibulin-5沉积增加,后者至少部分是通过醛固酮诱导的TGF-β1引起的。
5.醛固酮的上述作用是醛固酮与MR结合后对主动脉的直接作用,与醛固酮的血压升高效应无关。
Background
Primary aldosteronism (PA), mainly deriving from adrenal aldosterone-producing adenoma (APA), is the most common cause of secondary hypertension. However, even after the resection of adenomas, a part of patients still suffer from hypertension, which is possibly due to irreversible vascular remodeling. Aldosterone is traditionally believed to be produced in the adrenal cortex and elevates BP through renal effects on sodium and water retention via binding to the mineralocorticoid receptor (MR). However, it was recently reported that blood vessels per se produced aldosterone and synthesized MRs and 11-β-hydroxysteroid-dehydrogenase-2, an essential enzyme for aldosterone specifically binding to MRs. Thus, blood vessels possess a complete system for aldosterone activity. a lot of studies have shown that aldosterne induces vascular oxidative stress, inflammation and fibrosis, resulting in vascular damage and remodeling.
In in vitro studies, aldsoterone was shown to stimulate vascular smooth muscle cell (VSMC) proliferation. MDM2, a mediator that promotes cell proliferation mainly by forming a complex with p53 and inhibiting p53-mediated G1 and G2 cell cycle arrest and apoptosis. Recently, Nakamura et al. reported that aldosterone induced MDM2 expression in aortic smooth muscel cells by mineralocorticoid receptors. Moreover, after suppressing MDM2 expression, the effect of aldosterone on VSMC proliferation was also inhibited. Our previous study showed that aldosterone induced MDM2 expression in the aorta in vivo. However, whether aldosterone induces VSMC proliferation in vivo as well as the roles of MDM2 and p53 in the proliferation effect of aldosterone need to be elucidated.
In addition to VSMC proliferation, previous studies have shown that aldsoterone induces vascular oxidative stress, inflammation and fibrosis, resulting in vascular damage and remodeling. Recently, aldosterone was demonstrated to induce the apoptosis of several types of cells. In addition, deoxycorticosterone acetate (DOCA)-salt rats, another animal model of excessive mineralocorticoid, presented with increased apoptotic vascular smooth muscle cells (VSMCs) in the aorta. Moreover, transgenic Ren2 rats with elevated plasma aldosterone concentration and angiotensin II activity exhibited more apoptotic vascular cells in the aorta than normal rats. Nevertheless, whether aldosterone stimulates aortic apoptosis in vivo is unknown.
Besides, aldosterone also promotes extracellular matrix (ECM) deposition. Fibulin-5, a secreted (ECM) glycoprotein, is the new member of fibulin family. Recent studies have identified fibulin-5 as an essential protein for elastic fiber assembly. Inactivation of the fibulin-5 gene in mice results in a generalized elastinaopathy affecting those organs with abundant elastic fibers including blood vessels. Fibulin-5 was shown to be involved in phlebosclerosis of major portal vein branches associated with elastic fiber deposition in idiopathic portal hypertension. In contrast, decreased expression of fibulin-5 correlating with reduced elastin in thoracic aortic dissection was found. Compared with wild type cells, VSMCs from fibulin-5-/- mices demonstrated more proliferation and migration under the stimulation of mitogen, which could be inhibited after overexpression of fibulin-5, suggesting that fibulin-5 is a suppressor of proliferation and migration. Studies demonstrated the lack of fibulin-5 mRNA in most malignant tumors, implying that fubulin-5 acts as a suppressor in most cancers. Therefore, fibulin-5 is a multfunctional protein. Fibulin-5 was reported to be a new target gene of TGF-β1 that induces fibulin-5 expression in fibroblasts and endothelial cells.
In the current study, we first constructed rat models of APAs by subcutaneously implanting osmotic mini-pumps in rats. After 8 week infusion of aldosterone, aortic morphology was observed. Then we examined the status of aortic proliferation and apoptosis as well as the expressions of proliferation and apoptosis-related genes. Finally, we evaluated the effects of aldosterone on fibulin-5 deposition and TGF-β1 expression in the aorta. Relative to spironolactone, eplerenone is a specific mineralocorticoid receptor (MR) blocker, which can enhance the selectivity of binding MRs and reduce the side effects by spironolactone. Hydralazine is an old drug used for the treatment of hypertension by directly dilating the resistance arteries with minor effects on aortas. In the present study, we take use of the two drugs to interfere the effect of aldosteone on the aorta to explore the mechanisms of aortic damage by aldosterone.
Methods
1.32 Sprague-Dawley rats, each subcutaneously implanted with an osmotic mini-pump, were randomly divided into 4 groups:vehicle as control; aldosterone (1μg/h); aldosterone plus eplerenone (100 mg/kg/day) and aldosterone plus hydralazine (25 mg/kg/day). Because Alzet 2004 minipump continuously infuses the test substances only for 4 weeks, another minipump was implanted after the fourth week to realize the goal of 8 week effect of aldosterone on rats. Eplerenone and hydralazine were dissolved in drinking water. Systolic blood pressure (SBP) was measured weekly by the tail-cuff method. At the termination of the study, blood was collected for measurements of plasma renin activity (PRA) and aldosterone concontration (PAC) with radioimmunoassay kits. Then, media width (MW) and cross sectional area (MCSA) of the aortas were measured.
2. After 8 weeks, the PCNA-positive VSMCs and PCNA expression level in the aorta were examined by immunohistochemistry and Western blotting. In addition, the expressions of MDM2 and p53 genes were examined by immunohistochemistry, RT-PCR and Western blotting.
3. Apoptosis was examined by TUNEL assay. The levels of cytochrome c and caspase-3 were determined by Western blotting and the expressions of Bax and Bcl-2 were evaluated by immnuohistochemistry and Western blotting.
4. The expressions of fibulin-5 and TGF-β1 were examined by immnuohistochemistry and Western blotting.
Results
1. Rat models of APAs were successfully established. SBP was similar among the groups at the beginning of the experiment. After 3 weeks, aldosterone-infused rats showed significantly and progressively increased SBP compared with controls (P<0.05). The increase was significantly but incompletely inhibited after treatment with eplerenone or hydralazine (P<0.05). As expected, PAC was significantly increased with significantly depressed PRA in APA rats; and both were unaffected by eplerenone or hydralazine.
2. The MW and MCSA of the aorta in APA rats had a trend to increase relative to those of control rats. However, the increase did not achieve statistical significance(P=0.108; P=0.068, respectively).
3. Compared with controls, APA rats showed more PCNA-positive cells and higher PCNA expression (p<0.01). Upregulated expressions of both MDM2 mRNA and protein were shown in the aorta, associated with elevated p53 protien (P<0.05).4. Compared with controls, APA rats exhibited elevated aortic vascular cell apoptosis accompanied with higher levels of cytochrome c and activated caspase-3 as well as significantly upregulated Bax and downregulated Bcl-2.
4. Relative to control rats, APA rats exhibited increases in fibulin-5 deposition and TGF-β1 expression.
5. All the above effects of aldosterone on the aorta were significantly inhibited after co-administration with eplerenone but not with hydralazine.
Conclusions
1. By subcutaneously implanting osmotic minipumps in rats, the rat models of APAs can be successfully established, providing a good platform for investigating the pathogenesis of APAs.
2. Aldosterone promotes aortic VSMC proliferation, which contributes to aldosterone-induced vascular remodeling, at least partially by upregulating the expression of MDM2 that is able to inhibit the effect of cell cylcle arrest of simultaneously elevated p53.
3. Aldosterone induces vascular cell apoptosis in vivo, which may contribute to aldosterone-mediated aortic injury.
4. Aldosterone directly promotes aortic deposition of fibulin-5 that is at least partially stimulated by aldsoterone-induced TGF-β1.
5. All the above effects of aldosterone on the aorta are the direct effects of aldosterone via MRs and independently of the aldosterone-mediated increase of blood pressure.
引文
[1]Ganguly A. Primary aldosteronism. NEngl J Med.1998;339:1828-1834.
[2]Gordon RD, Stowasser M, Rutherford JC. Primary aldosteronism:are we diagnosing and operating on too few patients? World JSurg.2001;25:941-947.
[3]Young WF, Jr. Minireview:primary aldosteronism--changing concepts in diagnosis and treatment. Endocrinology.2003;144:2208-2213.
[4]Mulatero P, Stowasser M, Loh KC, et al. Increased diagnosis of primary aldosteronism, including surgically correctable forms, in centers from five continents. J Clin Endocrinol Metab.2004;89:1045-1050.
[5]Lumachi F, Ermani M, Basso SM, et al. Long-term results of adrenalectomy in patients with aldosterone-producing adenomas:multivariate analysis of factors affecting unresolved hypertension and review of the literature. Am Surg.2005;71:864-869.
[6]Meyer A, Brabant G, Behrend M. Long-term follow-up after adrenalectomy for primary aldosteronism. World J Surg.2005;29:155-159.
[7]Rossi G, Boscaro M, Ronconi V, et al. Aldosterone as a cardiovascular risk factor. Trends Endocrinol Metab.2005;16:104-107.
[8]Strauch B, Petrak O, Wichterle D, et al. Increased arterial wall stiffness in primary aldosteronism in comparison with essential hypertension. Am J Hypertens.2006;19: 909-914.
[9]Rossi GP, Bolognesi M, Rizzoni D, et al. Vascular remodeling and duration of hypertension predict outcome of adrenalectomy in primary aldosteronism patients. Hypertension.2008;51:1366-1371.
[10]Hatakeyama H, Miyamori I, Fujita T, et al. Vascular aldosterone. Biosynthesis and a link to angiotensin II-induced hypertrophy of vascular smooth muscle cells. J Biol Chem.1994;269:24316-24320.
[11]Funder JW, Pearce PT, Smith R, et al. Vascular type Ⅰ aldosterone binding sites are physiological mineralocorticoid receptors. Endocrinology.1989;125:2224-2226.
[12]Hatakeyama H, Inaba S, Takeda R, et al. llbeta-hydroxysteroid dehydrogenase in human vascular cells. Kidney Int.2000;57:1352-1357.
[13]Ishizawa K, Izawa Y, Ito H, et al. Aldosterone stimulates vascular smooth muscle cell proliferation via big mitogen-activated protein kinase 1 activation. Hypertension. 2005;46:1046-1052.
[14]Xiao F, Puddefoot JR, Barker S, et al. Mechanism for aldosterone potentiation of angiotensin II-stimulated rat arterial smooth muscle cell proliferation. Hypertension. 2004;44:340-345.
[15]Nakamura Y, Suzuki S, Suzuki T, et al. MDM2:a novel mineralocorticoid-responsive gene involved in aldosterone-induced human vascular structural remodeling. Am J Pathol.2006;169:362-371.
[16]王超,闫永吉,欧阳金芝等.鼠双微体-2基因在醛固酮增多症大鼠模型主动脉平滑肌中的表达.中华实验外科杂志.2009;26：630-632.
[17]Olson DC, Marechal V, Momand J, et al. Identification and characterization of multiple mdm-2 proteins and mdm-2-p53 protein complexes. Oncogene.1993;8: 2353-2360.
[18]Meulmeester E, Jochemsen AG p53:a guide to apoptosis. Curr Cancer Drug Targets. 2008;8:87-97.
[19]Patni H, Mathew JT, Luan L, et al. Aldosterone promotes proximal tubular cell apoptosis: role of oxidative stress. Am JPhysiol Renal Physiol.2007;293:F1065-1071.
[20]Mathew JT, Patni H, Chaudhary AN, et al. Aldosterone induces mesangial cell apoptosis both in vivo and in vitro. Am J Physiol Renal Physiol.2008;295:F73-81.
[21]Hayashi H, Kobara M, Abe M, et al. Aldosterone nongenomically produces NADPH oxidase-dependent reactive oxygen species and induces myocyte apoptosis. Hypertens Res.2008;31:363-375.
[22]Sharifi AM, Schiffrin EL. Apoptosis in aorta of deoxycorticosterone acetate-salt hypertensive rats:effect of endothelin receptor antagonism. J Hypertens.1997; 15: 1441-1448.
[23]Wei Y, Whaley-Connell AT, Habibi J, et al. Mineralocorticoid receptor antagonism attenuates vascular apoptosis and injury via rescuing protein kinase B activation. Hypertension.2009;53:158-165.
[24]Timpl R, Sasaki T, Kostka G, et al. Fibulins:a versatile family of extracellular matrix proteins. Nat Rev Mol Cell Biol.2003;4:479-489.
[25]Argraves WS, Greene LM, Cooley MA, et al. Fibulins:physiological and disease perspectives. EMBO Rep.2003;4:1127-1131.
[26]Loeys B, Van Maldergem L, Mortier G, et al. Homozygosity for a missense mutation in fibulin-5 (FBLN5) results in a severe form of cutis laxa. Hum Mol Genet.2002;11: 2113-2118.
[27]de Schepper S, Loeys B, de Paepe A, et al. Cutis laxa of the autosomal recessive type in a consanguineous family. Eur JDermatol.2003;13:529-533.
[28]Markova D, Zou Y, Ringpfeil F, et al. Genetic heterogeneity of cutis laxa:a heterozygous tandem duplication within the fibulin-5 (FBLN5) gene. Am J Hum Genet.2003;72:998-1004.
[29]Nakamura T, Lozano PR, Ikeda Y, et al. Fibulin-5/DANCE is essential for elastogenesis in vivo. Nature.2002;415:171-175.
[30]Yanagisawa H, Davis EC, Starcher BC, et al. Fibulin-5 is an elastin-binding protein essential for elastic fibre development in vivo. Nature.2002;415:168-171.
[31]Stone EM, Braun TA, Russell SR, et al. Missense variations in the fibulin 5 gene and age-related macular degeneration. NEngl J Med.2004;351:346-353.
[32]Sato Y, Sawada S, Nakanuma Y. Fibulin-5 is involved in phlebosclerosis of major portal vein branches associated with elastic fiber deposition in idiopathic portal hypertension. Hepatol Res.2008;38:166-173.
[33]Wang X, LeMaire SA, Chen L, et al. Decreased expression of fibulin-5 correlates with reduced elastin in thoracic aortic dissection. Surgery.2005;138:352-359.
[34]Spencer JA, Hacker SL, Davis EC, et al. Altered vascular remodeling in fibulin-5-deficient mice reveals a role of fibulin-5 in smooth muscle cell proliferation and migration. Proc Natl Acad Sci USA.2005;102:2946-2951.
[35]Schiemann WP, Blobe GC, Kalume DE, et al. Context-specific effects of fibulin-5 (DANCE/EVEC) on cell proliferation, motility, and invasion. Fibulin-5 is induced by transforming growth factor-beta and affects protein kinase cascades. J Biol Chem. 2002;277:27367-27377.
[36]Katsuta Y, Ogura Y, Iriyama S, et al. Fibulin-5 accelerates elastic fibre assembly in human skin fibroblasts. Exp Dermatol.2008;17:837-842.
[1]Ganguly A. Primary aldosteronism. N Engl J Med.1998;339:1828-1834.
[2]Young WF, Jr. Minireview:primary aldosteronism--changing concepts in diagnosis and treatment. Endocrinology.2003;144:2208-2213.
[3]Lumachi F, Ermani M, Basso SM, et al. Long-term results of adrenalectomy in patients with aldosterone-producing adenomas:multivariate analysis of factors affecting unresolved hypertension and review of the literature. Am Surg. 2005;71:864-869.
[4]Meyer A, Brabant G, Behrend M. Long-term follow-up after adrenalectomy for primary aldosteronism. World JSurg.2005;29:155-159.
[5]Ishizawa K, Izawa Y, Ito H, et al. Aldosterone stimulates vascular smooth muscle cell proliferation via big mitogen-activated protein kinase 1 activation. Hypertension.2005;46:1046-1052.
[6]Xiao F, Puddefoot JR, Barker S, et al. Mechanism for aldosterone potentiation of angiotensin II-stimulated rat arterial smooth muscle cell proliferation. Hypertension. 2004;44:340-345.
[7]Nakamura Y, Suzuki S, Suzuki T, et al. MDM2:a novel mineralocorticoid-responsive gene involved in aldosterone-induced human vascular structural remodeling. Am J Pathol.2006;169:362-371.
[8]王超,闫永吉,欧阳金芝等.鼠双微体-2基因在醛固酮增多症大鼠模型主动脉平滑肌中的表达.中化实验外科杂志.2009;26：630-632.
[9]Iwakuma T, Lozano G MDM2, an introduction. Mol Cancer Res.2003; 1:993-1000.
[10]Mulatero P, Stowasser M, Loh KC, et al. Increased diagnosis of primary aldosteronism, including surgically correctable forms, in centers from five continents. J Clin Endocrinol Metab.2004;89:1045-1050.
[11]Hatakeyama H, Miyamori I, Fujita T, et al. Vascular aldosterone. Biosynthesis and a link to angiotensin II-induced hypertrophy of vascular smooth muscle cells. J Biol Chem.1994;269:24316-24320.
[12]Funder JW, Pearce PT, Smith R, et al. Vascular type I aldosterone binding sites are physiological mineralocorticoid receptors. Endocrinology.1989;125:2224-2226.
[13]Hatakeyama H, Inaba S, Takeda R, et al. llbeta-hydroxysteroid dehydrogenase in human vascular cells. Kidney Int.2000;57:1352-1357.
[14]Lacolley P, Labat C, Pujol A, et al. Increased carotid wall elastic modulus and flbronectin in aldosterone-salt-treated rats:effects of eplerenone. Circulation. 2002;106:2848-2853.
[15]Park JB, Schiffrin EL. ET(A) receptor antagonist prevents blood pressure elevation and vascular remodeling in aldosterone-infused rats. Hypertension.2001;37:1444-1449.
[16]Iglarz M, Touyz RM, Viel EC, et al. Involvement of oxidative stress in the profibrotic action of aldosterone. Interaction wtih the renin-angiotension system. Am J Hypertens.2004;17:597-603.
[17]Meulmeester E, Jochemsen AG p53:a guide to apoptosis. Curr Cancer Drug Targets.2008;8:87-97.
[18]Martinet W, Knaapen MW, De Meyer GR, et al. Elevated levels of oxidative DNA damage and DNA repair enzymes in human atherosclerotic plaques. Circulation. 2002;106:927-932.
[19]Lopez-Candales A, Holmes DR, Liao S, et al. Decreased vascular smooth muscle cell density in medial degeneration of human abdominal aortic aneurysms. Am J Pathol.1997;150:993-1007.
[20]Brown NJ. Aldosterone and vascular inflammation. Hypertension.2008;51:161-167.
[21]Fritsche M, Haessler C, Brandner G Induction of nuclear accumulation of the tumor-suppressor protein p53 by DNA-damaging agents. Oncogene.1993;8:307-318.
[22]Chehab NH, Malikzay A, Stavridi ES, et al. Phosphorylation of Ser-20 mediates stabilization of human p53 in response to DNA damage. Proc Natl Acad Sci U S A. 1999;96:13777-13782.
[23]Vousden KH, Lu X. Live or let die:the cell's response to p53. Nat Rev Cancer. 2002;2:594-604.
[24]Ries S, Biederer C, Woods D, et al. Opposing effects of Ras on p53:transcriptional activation of mdm2 and induction of p19ARF. Cell.2000;103:321-330.
[25]Candeias MM, Malbert-Colas L, Powell DJ, et al. P53 mRNA controls p53 activity by managing Mdm2 functions. Nat Cell Biol.2008;10:1098-1105.
[26]Ihling C, Haendeler J, Menzel G, et al. Co-expression of p53 and MDM2 in human atherosclerosis:implications for the regulation of cellularity of atherosclerotic lesions. J Pathol. 1998;185:303-312.
[27]Fuller PJ, Young MJ. Mechanisms of mineralocorticoid action. Hypertension. 2005;46:1227-1235.
[1]Milliez P, Girerd X, Plouin PF, et al. Evidence for an increased rate of cardiovascular events in patients with primary aldosteronism. J Am Coll Cardiol. 2005;45:1243-1248.
[2]Amano T, Matsubara T, Izawa H, et al. Impact of plasma aldosterone levels for prediction of in-stent restenosis. Am J Cardiol.2006;97:785-788.
[3]Pitt B, Remme W, Zannad F, et al. Eplerenone, a selective aldosterone blocker, in patients with left ventricular dysfunction after myocardial infarction. N Engl J Med. 2003;348:1309-1321.
[4]Fuller PJ, Young MJ. Mechanisms of mineralocorticoid action. Hypertension. 2005;46:1227-1235.
[5]Hatakeyama H, Miyamori I, Fujita T, et al. Vascular aldosterone. Biosynthesis and a link to angiotensin II-induced hypertrophy of vascular smooth muscle cells. J Biol Chem.1994;269:24316-24320.
[6]Funder JW, Pearce PT, Smith R, et al. Vascular type I aldosterone binding sites are physiological mineralocorticoid receptors. Endocrinology.1989;125:2224-2226.
[7]Hatakeyama H, Inaba S, Takeda R, et al. llbeta-hydroxysteroid dehydrogenase in human vascular cells. Kidney Int.2000;57:1352-1357.
[8]Callera GE, Touyz RM, Tostes RC, et al. Aldosterone activates vascular p38MAP kinase and NADPH oxidase via c-Src. Hypertension.2005;45:773-779.
[9]Hirono Y, Yoshimoto T, Suzuki N, et al. Angiotensin II receptor type 1-mediated vascular oxidative stress and proinflammatory gene expression in aldosterone-induced hypertension:the possible role of local renin-angiotensin system. Endocrinology.2007;148:1688-1696.
[10]Iglarz M, Touyz RM, Viel EC, et al. Involvement of oxidative stress in the profibrotic action of aldosterone. Interaction wtih the renin-angiotension system. Am J Hypertens.2004;17:597-603.
[11]Lopez-Candales A, Holmes DR, Liao S, et al. Decreased vascular smooth muscle cell density in medial degeneration of human abdominal aortic aneurysms. Am J Pathol.1997;150:993-1007.
[12]von der Thusen JH, van Vlijmen BJ, Hoeben RC, et al. Induction of atherosclerotic plaque rupture in apolipoprotein E-/-mice after adenovirus-mediated transfer of p53. Circulation.2002;105:2064-2070.
[13]Korshunov VA, Berk BC. Smooth muscle apoptosis and vascular remodeling. Curr Opin Hematol.2008;15:250-254.
[14]Durand E, Scoazec A, Lafont A, et al. In vivo induction of endothelial apoptosis leads to vessel thrombosis and endothelial denudation:a clue to the understanding of the mechanisms of thrombotic plaque erosion. Circulation.2004;109:2503-2506.
[15]Patni H, Mathew JT, Luan L, et al. Aldosterone promotes proximal tubular cell apoptosis:role of oxidative stress. Am J Physiol Renal Physiol.2007;293: F1065-1071.
[16]Mathew JT, Patni H, Chaudhary AN, et al. Aldosterone induces mesangial cell apoptosis both in vivo and in vitro. Am J Physiol Renal Physiol.2008;295:F73-81.
[17]Hayashi H, Kobara M, Abe M, et al. Aldosterone nongenomically produces NADPH oxidase-dependent reactive oxygen species and induces myocyte apoptosis. Hypertens Res.2008;31:363-375.
[18]Sharifi AM, Schiffrin EL. Apoptosis in aorta of deoxycorticosterone acetate-salt hypertensive rats:effect of endothelin receptor antagonism. J Hypertens.1997;15: 1441-1448.
[19]Wei Y, Whaley-Connell AT, Habibi J, et al. Mineralocorticoid receptor antagonism attenuates vascular apoptosis and injury via rescuing protein kinase B activation. Hypertension.2009;53:158-165.
[20]Lumachi F, Ermani M, Basso SM, et al. Long-term results of adrenalectomy in patients with aldosterone-producing adenomas:multivariate analysis of factors affecting unresolved hypertension and review of the literature. Am Surg. 2005;71:864-869.
[21]Struthers A, Krum H, Williams GH. A comparison of the aldosterone-blocking agents eplerenone and spironolactone. Clin Cardiol.2008;31:153-158.
[22]Williams TA, Verhovez A, Milan A, et al. Protective effect of spironolactone on endothelial cell apoptosis. Endocrinology.2006;147:2496-2505.
[23]Li Y, Song YH, Mohler J, et al. ANG Ⅱ induces apoptosis of human vascular smooth muscle via extrinsic pathway involving inhibition of Akt phosphorylation and increased FasL expression. Am J Physiol Heart Circ Physiol.2006;290: H2116-2123.
[24]Li PF, Dietz R, von Harsdorf R. Differential effect of hydrogen peroxide and superoxide anion on apoptosis and proliferation of vascular smooth muscle cells. Circulation.1997;96:3602-3609.
[25]Mercer J, Mahmoudi M, Bennett M. DNA damage, p53, apoptosis and vascular disease. Mutat Res.2007;621:75-86.
[26]Kutuk O, Basaga H. Bcl-2 protein family:implications in vascular apoptosis and atherosclerosis. Apoptosis.2006; 11:1661-1675.
[27]Oltvai ZN, Milliman CL, Korsmeyer SJ. Bcl-2 heterodimerizes in vivo with a conserved homolog, Bax, that accelerates programmed cell death. Cell.1993;74: 609-619.
[1]Hueber AO, Evan GI. Traps to catch unwary oncogenes. Trends Genet. 1998;14:364-367.
[2]Mathew JT, Patni H, Chaudhary AN, et al. Aldosterone induces mesangial cell apoptosis both in vivo and in vitro. Am JPhysiol Renal Physiol.2008;295:F73-81.
[3]Hamet P. Proliferation and apoptosis of vascular smooth muscle in hypertension. Curr Opin Nephrol Hypertens.1995;4:1-7.
[4]Sharifi AM, Schiffrin EL. Apoptosis in aorta of deoxycorticosterone acetate-salt hypertensive rats:effect of endothelin receptor antagonism. J Hypertens.1997; 15: 1441-1448.
[5]Sharifi AM, Schiffrin EL. Apoptosis in vasculature of spontaneously hypertensive rats:effect of an angiotensin converting enzyme inhibitor and a calcium channel antagonist. Am J Hypertens.1998;11:1108-1116.
[6]Korshunov VA, Berk BC. Smooth muscle apoptosis and vascular remodeling. Curr Opin Hematol.2008;15:250-254.
[7]Rossig L, Dimmeler S, Zeiher AM. Apoptosis in the vascular wall and atherosclerosis. Basic Res Cardiol.2001;96:11-22.
[8]Durand E, Scoazec A, Lafont A, et al. In vivo induction of endothelial apoptosis leads to vessel thrombosis and endothelial denudation:a clue to the understanding of the mechanisms of thrombotic plaque erosion. Circulation.2004;109:2503-2506.
[9]Vousden KH, Lu X. Live or let die:the cell's response to p53. Nat Rev Cancer. 2002;2:594-604.
[10]Meulmeester E, Jochemsen AG p53:a guide to apoptosis. Curr Cancer Drug Targets.2008;8:87-97.
[11]Ihling C, Haendeler J, Menzel G, et al. Co-expression of p53 and MDM2 in human atherosclerosis:implications for the regulation of cellularity of atherosclerotic lesions. JPathol.1998;185:303-312.
[12]Thornborrow EC, Patel S, Mastropietro AE, et al. A conserved intronic response element mediates direct p53-dependent transcriptional activation of both the human
and murine bax genes. Oncogene.2002;21:990-999.
[13]Miyashita T, Harigai M, Hanada M, et al. Identification of a p53-dependent negative response element in the bcl-2 gene. Cancer Res.1994;54:3131-3135.
[14]Schnackenberg CG, Welch WJ, Wilcox CS. Normalization of blood pressure and renal vascular resistance in SHR with a membrane-permeable superoxide dismutase mimetic:role of nitric oxide. Hypertension.1998;32:59-64.
[15]Munzel T, Kurz S, Rajagopalan S, et al. Hydralazine prevents nitroglycerin tolerance by inhibiting activation of a membrane-bound NADH oxidase. A new action for an old drug.J Clin Invest.1996;98:1465-1470.
[16]Milliez P, Girerd X, Plouin PF, et al. Evidence for an increased rate of cardiovascular events in patients with primary aldosteronism. J Am Coll Cardiol. 2005;45:1243-1248.
[17]Lumachi F, Ermani M, Basso SM, et al. Long-term results of adrenalectomy in patients with aldosterone-producing adenomas:multivariate analysis of factors affecting unresolved hypertension and review of the literature. Am Surg. 2005;71:864-869.
[1]Mulatero P, Stowasser M, Loh KC, et al. Increased diagnosis of primary aldosteronism, including surgically correctable forms, in centers from five continents. J Clin Endocrinol Metab.2004;89:1045-1050.
[2]Lumachi F, Ermani M, Basso SM, et al. Long-term results of adrenalectomy in patients with aldosterone-producing adenomas:multivariate analysis of factors affecting unresolved hypertension and review of the literature. Am Surg. 2005;71:864-869.
[3]Fuller PJ, Young MJ. Mechanisms of mineralocorticoid action. Hypertension. 2005;46:1227-1235.
[4]Schiffrin EL. Effects of aldosterone on the vasculature. Hypertension.2006;47: 312-318.
[5]Ishizawa K, Izawa Y, Ito H, et al. Aldosterone stimulates vascular smooth muscle cell proliferation via big mitogen-activated protein kinase 1 activation. Hypertension.2005;46:1046-1052.
[6]Iglarz M, Touyz RM, Viel EC, et al. Involvement of oxidative stress in the profibrotic action of aldosterone. Interaction wtih the renin-angiotension system. Am J Hypertens.2004;17:597-603.
[7]Pu Q, Neves MF, Virdis A, et al. Endothelin antagonism on aldosterone-induced oxidative stress and vascular remodeling. Hypertension.2003;42:49-55.
[8]Lacolley P, Labat C, Pujol A, et al. Increased carotid wall elastic modulus and fibronectin in aldosterone-salt-treated rats:effects of eplerenone. Circulation. 2002; 106:2848-2853.
[9]Timpl R, Sasaki T, Kostka G, et al. Fibulins:a versatile family of extracellular matrix proteins. Nat Rev Mol Cell Biol.2003;4:479-489.
[10]Argraves WS, Greene LM, Cooley MA, et al. Fibulins:physiological and disease perspectives. EMBO Rep.2003;4:1127-1131.
[11]Loeys B, Van Maldergem L, Mortier G, et al. Homozygosity for a missense mutation in fibulin-5 (FBLN5) results in a severe form of cutis laxa. Hum Mol
Genet.2002;11:2113-2118.
[12]de Schepper S, Loeys B, de Paepe A, et al. Cutis laxa of the autosomal recessive type in a consanguineous family. Eur JDermatol.2003;13:529-533.
[13]Markova D, Zou Y, Ringpfeil F, et al. Genetic heterogeneity of cutis laxa:a heterozygous tandem duplication within the fibulin-5 (FBLN5) gene. Am J Hum Genet.2003;72:998-1004.
[14]Nakamura T, Lozano PR, Ikeda Y, et al. Fibulin-5/DANCE is essential for elastogenesis in vivo. Nature.2002;415:171-175.
[15]Yanagisawa H, Davis EC, Starcher BC, et al. Fibulin-5 is an elastin-binding protein essential for elastic fibre development in vivo. Nature.2002;415:168-171.
[16]Stone EM, Braun TA, Russell SR, et al. Missense variations in the fibulin 5 gene and age-related macular degeneration. N Engl J Med.2004;351:346-353.
[17]Sato Y, Sawada S, Nakanuma Y. Fibulin-5 is involved in phlebosclerosis of major portal vein branches associated with elastic fiber deposition in idiopathic portal hypertension. Hepatol Res.2008;38:166-173.
[18]Merklinger SL, Wagner RA, Spiekerkoetter E, et al. Increased fibulin-5 and elastin in S100A4/Mtsl mice with pulmonary hypertension. Ore Res.2005;97:596-604.
[19]Kuang PP, Goldstein RH, Liu Y, et al. Coordinate expression of fibulin-5/DANCE and elastin during lung injury repair. Am J Physiol Lung Cell Mol Physiol. 2003;285:L1147-1152.
[20]Wang X, LeMaire SA, Chen L, et al. Decreased expression of fibulin-5 correlates with reduced elastin in thoracic aortic dissection. Surgery.2005;138:352-359.
[21]Spencer JA, Hacker SL, Davis EC, et al. Altered vascular remodeling in fibulin-5-deficient mice reveals a role of fibulin-5 in smooth muscle cell proliferation and migration. Proc Natl Acad Sci USA.2005;102:2946-2951.
[22]Nakamura T, Ruiz-Lozano P, Lindner V, et al. DANCE, a novel secreted RGD protein expressed in developing, atherosclerotic, and balloon-injured arteries. J Biol Chem.1999;274:22476-22483.
[23]Schiemann WP, Blobe GC, Kalume DE, et al. Context-specific effects of fibulin-5 (DANCE/EVEC) on cell proliferation, motility, and invasion. Fibulin-5 is induced by transforming growth factor-beta and affects protein kinase cascades. J Biol Chem. 2002;277:27367-27377.
[24]Katsuta Y, Ogura Y, Iriyama S, et al. Fibulin-5 accelerates elastic fibre assembly in human skin fibroblasts. Exp Dermatol.2008;17:837-842.
[25]Funder J, Carey R, Fardella C, et al. Case detection, diagnosis, and treatment of patients with primary aldosteronism:an Endocrine Society clinical practice guideline. Eur J Endocrinol.2009.
[26]Safar ME. Systolic blood pressure, pulse pressure and arterial stiffness as cardiovascular risk factors. Curr Opin Nephrol Hypertens.2001;10:257-261.
[27]Seyrek N, Balal M, Karayaylali I, et al. Which parameter is more influential on the development of arteriosclerosis in hemodialysis patients? Ren Fail. 2003;25:1011-1018.
[28]Midwood KS, Schwarzbauer JE. Elastic fibers:building bridges between cells and their matrix. Curr Biol.2002;12:R279-281.
[29]Kielty CM, Sherratt MJ, Shuttleworth CA. Elastic fibres. J Cell Sci.2002;115: 2817-2828.
[30]Kowal RC, Richardson JA, Miano JM, et al. EVEC, a novel epidermal growth factor-like repeat-containing protein upregulated in embryonic and diseased adult vasculature. Circ Res.1999;84:1166-1176.
[31]Nguyen AD, Itoh S, Jeney V, et al. Fibulin-5 is a novel binding protein for extracellular superoxide dismutase. Circ Res.2004;95:1067-1074.
[32]Brown NJ. Aldosterone and vascular inflammation. Hypertension.2008;51:161-167.
[33]Zhao YD, Campbell AI, Robb M, et al. Protective role of angiopoietin-1 in experimental pulmonary hypertension. Circ Res.2003;92:984-991.
[34]Juknevicius I, Segal Y, Kren S, et al. Effect of aldosterone on renal transforming growth factor-beta. Am JPhysiol Renal Physiol.2004;286:F 1059-1062.
[35]Wakida N, Kitamura K, Tuyen DG, et al. Inhibition of prostasin-induced ENaC activities by PN-1 and regulation of PN-1 expression by TGF-betal and aldosterone. Kidney Int.2006;70:1432-1438.
[36]Sun GP, Kohno M, Guo P, et al. Involvements of Rho-kinase and TGF-beta pathways in aldosterone-induced renal injury. J Am Soc Nephrol.2006;17: 2193-2201.
[1]Trapp T, Holsboer F. Ligand-induced conformational changes in the mineralocorticoid receptor analyzed by protease mapping. Biochem Biophys Res Commun.1995;215:286-291.
[2]Fejes-Toth G, Pearce D, Naray-Fejes-Toth A. Subcellular localization of mineralocorticoid receptors in living cells:effects of receptor agonists and antagonists. Proc Natl Acad Sci USA.1998;95:2973-2978.
[3]Bhargava A, Fullerton MJ, Myles K, et al. The serum-and glucocorticoid-induced kinase is a physiological mediator of aldosterone action. Endocrinology.2001; 142: 1587-1594.
[4]Arriza JL, Weinberger C, Cerelli G, et al. Cloning of human mineralocorticoid receptor complementary DNA:structural and functional kinship with the glucocorticoid receptor. Science.1987;237:268-275.
[5]Chen SY, Bhargava A, Mastroberardino L, et al. Epithelial sodium channel regulated by aldosterone-induced protein sgk. Proc Natl Acad Sci U S A. 1999;96:2514-2519.
[6]Hatakeyama H, Miyamori I, Fujita T, et al. Vascular aldosterone. Biosynthesis and a link to angiotensin II-induced hypertrophy of vascular smooth muscle cells. J Biol Chem.1994;269:24316-24320.
[7]Takeda Y, Miyamori I, Yoneda T, et al. Regulation of aldosterone synthase in human vascular endothelial cells by angiotensin II and adrenocorticotropin. J Clin Endocrinol Metab.1996;81:2797-2800.
[8]Gomez-Sanchez CE, Zhou MY, Cozza EN, et al. Aldosterone biosynthesis in the rat brain. Endocrinology.1997;138:3369-3373.
[9]Silvestre JS, Robert V, Heymes C, et al. Myocardial production of aldosterone and corticosterone in the rat. Physiological regulation. J Biol Chem.1998;273: 4883-4891.
[10]Fuller PJ, Young MJ. Mechanisms of mineralocorticoid action. Hypertension. 2005;46:1227-1235.
[11]Losel RM, Falkenstein E, Feuring M, et al. Nongenomic steroid action: controversies, questions, and answers. Physiol Rev.2003;83:965-1016.
[12]Skott O, Uhrenholt TR, Schjerning J, et al. Rapid actions of aldosterone in vascular health and disease-friend or foe? Pharmacol Ther. 2006; 111:495-507.
[13]Pitt B, Zannad F, Remme WJ, et al. The effect of spironolactone on morbidity and mortality in patients with severe heart failure. Randomized Aldactone Evaluation Study Investigators. N Engl J Med.1999;341:709-717.
[14]Pitt B, Remme W, Zannad F, et al. Eplerenone, a selective aldosterone blocker, in patients with left ventricular dysfunction after myocardial infarction. N Engl J Med. 2003;348:1309-1321.
[15]Ramires FJ, Mansur A, Coelho O, et al. Effect of spironolactone on ventricular arrhythmias in congestive heart failure secondary to idiopathic dilated or to ischemic cardiomyopathy. Am J Cardiol.2000;85:1207-1211.
[16]Milliez P, Girerd X, Plouin PF, et al. Evidence for an increased rate of cardiovascular events in patients with primary aldosteronism. J Am Coll Cardiol. 2005;45:1243-1248.
[17]Rizzoni D, Porteri E, Castellano M, et al. Vascular hypertrophy and remodeling in secondary hypertension. Hypertension.1996;28:785-790.
[18]Safar ME, Cattan V, Lacolley P, et al. Aldosterone synthase gene polymorphism, stroke volume and age-related changes in aortic pulse wave velocity in subjects with hypertension. JHypertens.2005;23:1159-1166.
[19]Taddei S, Virdis A, Mattei P, et al. Vasodilation to acetylcholine in primary and secondary forms of human hypertension. Hypertension.1993;21:929-933.
[20]Nishizaka MK, Zaman MA, Green SA, et al. Impaired endothelium-dependent flow-mediated vasodilation in hypertensive subjects with hyperaldosteronism. Circulation.2004;109:2857-2861.
[21]Pu Q, Neves MF, Virdis A, et al. Endothelin antagonism on aldosterone-induced oxidative stress and vascular remodeling. Hypertension.2003;42:49-55.
[22]Arima S, Kohagura K, Xu HL, et al. Endothelium-derived nitric oxide modulates vascular action of aldosterone in renal arteriole. Hypertension.2004;43:352-357.
[23]Park JB, Schiffrin EL. ET(A) receptor antagonist prevents blood pressure elevation and vascular remodeling in aldosterone-infused rats. Hypertension.2001;37:1444-1449.
[24]Virdis A, Neves MF, Amiri F, et al. Spironolactone improves angiotensin-induced vascular changes and oxidative stress. Hypertension.2002;40:504-510.
[25]Romagni P, Rossi F, Guerrini L, et al. Aldosterone induces contraction of the resistance arteries in man. Atherosclerosis.2003; 166:345-349.
[26]Farquharson CA, Struthers AD. Aldosterone induces acute endothelial dysfunction in vivo in humans:evidence for an aldosterone-induced vasculopathy. Clin Sci (Lond).2002; 103:425-431.
[27]Davies JI, Band M, Morris A, et al. Spironolactone impairs endothelial function and heart rate variability in patients with type 2 diabetes. Diabetologia.2004;47: 1687-1694.
[28]Nishiyama A, Yao L, Nagai Y, et al. Possible contributions of reactive oxygen species and mitogen-activated protein kinase to renal injury in aldosterone/ salt-induced hypertensive rats. Hypertension.2004;43:841-848.
[29]Iglarz M, Touyz RM, Viel EC, et al. Involvement of oxidative stress in the profibrotic action of aldosterone. Interaction wtih the renin-angiotension system. Am J Hypertens.2004; 17:597-603.
[30]Blanco-Rivero J, Cachofeiro V, Lahera V, et al. Participation of prostacyclin in endothelial dysfunction induced by aldosterone in normotensive and hypertensive rats. Hypertension.2005;46:107-112.
[31]Nagata D, Takahashi M, Sawai K, et al. Molecular mechanism of the inhibitory effect of aldosterone on endothelial NO synthase activity. Hypertension. 2006;48:165-171.
[32]Vasquez-Vivar J, Kalyanaraman B, Martasek P, et al. Superoxide generation by endothelial nitric oxide synthase:the influence of cofactors. Proc Natl Acad Sci U S A.1998;95:9220-9225.
[33]Thai HM, Do BQ, Tran TD, et al. Aldosterone antagonism improves endothelial-dependent vasorelaxation in heart failure via upregulation of endothelial nitric oxide synthase production. J Card Fail.2006; 12:240-245.
[34]Calo LA, Zaghetto F, Pagnin E, et al. Effect of aldosterone and glycyrrhetinic acid on the protein expression of PAI-1 and p22(phox) in human mononuclear leukocytes. J Clin Endocrinol Metab.2004;89:1973-1976.
[35]Hirono Y, Yoshimoto T, Suzuki N, et al. Angiotensin Ⅱ receptor type 1-mediated vascular oxidative stress and proinflammatory gene expression in aldosterone-induced hypertension:the possible role of local renin-angiotensin system. Endocrinology.2007;148:1688-1696.
[36]Sanz-Rosa D, Oubina MP, Cediel E, et al. Eplerenone reduces oxidative stress and enhances eNOS in SHR:vascular functional and structural consequences. Antioxid Redox Signal.2005;7:1294-1301.
[37]Lariviere R, Thibault G, Schiffrin EL. Increased endothelin-1 content in blood vessels of deoxycorticosterone acetate-salt hypertensive but not in spontaneously hypertensive rats. Hypertension.1993;21:294-300.
[38]Arima S, Kohagura K, Xu HL, et al. Nongenomic vascular action of aldosterone in the glomerular microcirculation. J Am Soc Nephrol.2003;14:2255-2263.
[39]Fujita M, Minamino T, Asanuma H, et al. Aldosterone nongenomically worsens ischemia via protein kinase C-dependent pathways in hypoperfused canine hearts. Hypertension.2005;46:113-117.
[40]Liu SL, Schmuck S, Chorazcyzewski JZ, et al. Aldosterone regulates vascular reactivity:short-term effects mediated by phosphatidylinositol 3-kinase-dependent nitric oxide synthase activation. Circulation.2003; 108:2400-2406.
[41]Oberleithner H, Riethmuller C, Ludwig T, et al. Aldosterone remodels human endothelium. Acta Physiol (Oxf).2006;187:305-312.
[42]Petry A, Djordjevic T, Weitnauer M, et al. NOX2 and NOX4 mediate proliferative response in endothelial cells. Antioxid Redox Signal.2006;8:1473-1484.
[43]Paravicini TM, Touyz RM. Redox signaling in hypertension. Cardiovasc Res. 2006;71:247-258.
[44]Sun Y, Zhang J, Lu L, et al. Aldosterone-induced inflammation in the rat heart:role of oxidative stress. Am JPathol.2002; 161:1773-1781.
[45]Shibata S, Nagase M, Yoshida S, et al. Podocyte as the target for aldosterone:roles of oxidative stress and Sgk1. Hypertension.2007;49:355-364.
[46]Johar S, Cave AC, Narayanapanicker A, et al. Aldosterone mediates angiotensin Ⅱ-induced interstitial cardiac fibrosis via a Nox2-containing NADPH oxidase. Faseb J.2006;20:1546-1548.
[47]Stas S, Whaley-Connell A, Habibi J, et al. Mineralocorticoid receptor blockade attenuates chronic overexpression of the renin-angiotensin-aldosterone system stimulation of reduced nicotinamide adenine dinucleotide phosphate oxidase and cardiac remodeling. Endocrinology.2007; 148:3773-3780.
[48]Callera GE, Touyz RM, Tostes RC, et al. Aldosterone activates vascular p38MAP kinase and NADPH oxidase via c-Src. Hypertension.2005;45:773-779.
[49]Patni H, Mathew JT, Luan L, et al. Aldosterone promotes proximal tubular cell apoptosis:role of oxidative stress. Am J Physiol Renal Physiol.2007;293: F1065-1071.
[50]Leopold JA, Dam A, Maron BA, et al. Aldosterone impairs vascular reactivity by decreasing glucose-6-phosphate dehydrogenase activity. Nat Med.2007;13:189-197.
[51]Park YM, Park MY, Suh YL, et al. NAD(P)H oxidase inhibitor prevents blood pressure elevation and cardiovascular hypertrophy in aldosterone-infused rats. Biochem Biophys Res Commun.2004;313:812-817.
[52]Li L, Fink GD, Watts SW, et al. Endothelin-1 increases vascular superoxide via endothelin(A)-NADPH oxidase pathway in low-renin hypertension. Circulation. 2003;107:1053-1058.
[53]Callera GE, Montezano AC, Touyz RM, et al. ETA receptor mediates altered leukocyte-endothelial cell interaction and adhesion molecules expression in DOCA-salt rats. Hypertension.2004;43:872-879.
[54]Wong S, Brennan FE, Young MJ, et al. A direct effect of aldosterone on endothelin-1 gene expression in vivo. Endocrinology.2007; 148:1511-1517.
[55]Callera GE, Tostes RC, Yogi A, et al. Endothelin-1-induced oxidative stress in DOCA-salt hypertension involves NADPH-oxidase-independent mechanisms. Clin Sci (Lond).2006; 110:243-253.
[56]Hao L, Nishimura T, Wo H, et al. Vascular responses to alphal-adrenergic receptors in small rat mesenteric arteries depend on mitochondrial reactive oxygen species. Arterioscler Thromb Vasc Biol.2006;26:819-825.
[57]Ebata S, Muto S, Okada K, et al. Aldosterone activates Na+/H+ exchange in vascular smooth muscle cells by nongenomic and genomic mechanisms. Kidney Int. 1999;56:1400-1412.
[58]Rocha R, Chander PN, Zuckerman A, et al. Role of aldosterone in renal vascular injury in stroke-prone hypertensive rats. Hypertension.1999;33:232-237.
[59]Rocha R, Martin-Berger CL, Yang P, et al. Selective aldosterone blockade prevents angiotensin II/salt-induced vascular inflammation in the rat heart. Endocrinology. 2002; 143:4828-4836.
[60]Tostes RC, Touyz RM, He G, et al. Contribution of endothelin-1 to renal activator protein-1 activation and macrophage infiltration in aldosterone-induced hypertension. Clin Sci (Lond).2002; 103 Suppl 48:25S-30S.
[61]Young MJ, Moussa L, Dilley R, et al. Early inflammatory responses in experimental cardiac hypertrophy and fibrosis:effects of 11 beta-hydroxysteroid dehydrogenase inactivation. Endocrinology.2003;144:1121-1125.
[62]Rocha R, Rudolph AE, Frierdich GE, et al. Aldosterone induces a vascular inflammatory phenotype in the rat heart. Am J Physiol Heart Circ Physiol. 2002;283:H1802-1810.
[63]Young M, Funder JW. Eplerenone, but not steroid withdrawal, reverses cardiac fibrosis in deoxycorticosterone/salt-treated rats. Endocrinology.2004; 145:3153-3157.
[64]Pickering TG Stress, inflammation, and hypertension. J Clin Hypertens (Greenwich).2007;9:567-571.
[65]Irita J, Okura T, Manabe S, et al. Plasma osteopontin levels are higher in patients with primary aldosteronism than in patients with essential hypertension. Am J Hypertens.2006; 19:293-297.
[66]Scatena M, Liaw L, Giachelli CM. Osteopontin:a multifunctional molecule regulating chronic inflammation and vascular disease. Arterioscler Thromb Vasc Biol.2007;27:2302-2309.
[67]Clapp BR, Hirschfield GM, Storry C, et al. Inflammation and endothelial function: direct vascular effects of human C-reactive protein on nitric oxide bioavailability. Circulation.2005; 111:1530-1536.
[68]Luther JM, Gainer JV, Murphey LJ, et al. Angiotensin II induces interleukin-6 in humans through a mineralocorticoid receptor-dependent mechanism. Hypertension. 2006;48:1050-1057.
[69]Sawathiparnich P, Kumar S, Vaughan DE, et al. Spironolactone abolishes the relationship between aldosterone and plasminogen activator inhibitor-1 in humans. J Clin Endocrinol Metab.2002;87:448-452.
[70]Sawathiparnich P, Murphey LJ, Kumar S, et al. Effect of combined ATI receptor and aldosterone receptor antagonism on plasminogen activator inhibitor-1. J Clin Endocrinol Metab.2003;88:3867-3873.
[71]Ma J, Albornoz F, Yu C, et al. Differing effects of mineralocorticoid receptor-dependent and-independent potassium-sparing diuretics on fibrinolytic balance. Hypertension.2005;46:313-320.
[72]Gils A, Declerck PJ. Plasminogen activator inhibitor-1. Curr Med Chem. 2004; 11:2323-2334.
[73]Stefansson S, Lawrence DA. Old dogs and new tricks:proteases, inhibitors, and cell migration. Sci STKE.2003;2003:pe24.
[74]Brown NJ, Agirbasli MA, Williams GH, et al. Effect of activation and inhibition of the renin-angiotensin system on plasma PAI-1. Hypertension.1998;32:965-971.
[75]Takebayashi K, Matsumoto S, Aso Y, et al. Aldosterone blockade attenuates urinary monocyte chemoattractant protein-1 and oxidative stress in patients with type 2 diabetes complicated by diabetic nephropathy. J Clin Endocrinol Metab. 2006;91:2214-2217.
[76]Matsumoto S, Takebayashi K, Aso Y. The effect of spironolactone on circulating adipocytokines in patients with type 2 diabetes mellitus complicated by diabetic nephropathy. Metabolism.2006;55:1645-1652.
[77]Kasifoglu T, Yalcin AU. The effects of thiazide and thiazide-potassium sparing diuretics on fibrinolytic system parameters. Anadolu Kardiyol Derg.2006;6: 143-147.
[78]Ingelsson E, Pencina MJ, Tofler GH, et al. Multimarker approach to evaluate the incidence of the metabolic syndrome and longitudinal changes in metabolic risk factors:the Framingham Offspring Study. Circulation.2007; 116:984-992.
[79]Godfrey V, Farquharson CA, Macdonald JE, et al. Effect of spironolactone on C-reactive protein levels in patients with heart disease. Int J Cardiol.2007; 117: 282-284.
[80]Benetos A, Lacolley P, Safar ME. Prevention of aortic fibrosis by spironolactone in spontaneously hypertensive rats. Arterioscler Thromb Vasc Biol.1997; 17:1152-1156.
[81]Lacolley P, Labat C, Pujol A, et al. Increased carotid wall elastic modulus and fibronectin in aldosterone-salt-treated rats:effects of eplerenone. Circulation. 2002;106:2848-2853.
[82]Neves MF, Amiri F, Virdis A, et al. Role of aldosterone in angiotensin II-induced cardiac and aortic inflammation, fibrosis, and hypertrophy. Can J Physiol Pharmacol.2005;83:999-1006.
[83]Blasi ER, Rocha R, Rudolph AE, et al. Aldosterone/salt induces renal inflammation and fibrosis in hypertensive rats. Kidney Int.2003;63:1791-1800.
[84]Fiebeler A, Nussberger J, Shagdarsuren E, et al. Aldosterone synthase inhibitor ameliorates angiotensin II-induced organ damage. Circulation.2005; 111:3087-3094.
[85]Lam EY, Funder JW, Nikolic-Paterson DJ, et al. Mineralocorticoid receptor blockade but not steroid withdrawal reverses renal fibrosis in deoxycorticosterone/ salt rats. Endocrinology.2006;147:3623-3629.
[86]Guzik TJ, Hoch NE, Brown KA, et al. Role of the T cell in the genesis of angiotensin II induced hypertension and vascular dysfunction. J Exp Med. 2007;204:2449-2460.
[87]Sanz-Rosa D, Cediel E, de las Heras N, et al. Participation of aldosterone in the vascular inflammatory response of spontaneously hypertensive rats:role of the NFkappaB/IkappaB system. JHypertens.2005;23:1167-1172.
[88]de Winther MP, Kanters E, Kraal G, et al. Nuclear factor kappaB signaling in atherogenesis. Arterioscler Thromb Vasc Biol.2005;25:904-914.
[89]Armanini D, Kuhnle U, Witzgall H, et al. The determination of mineralocorticoid receptors in human mononuclear leukocytes from patients with mineralocorticoid excess:physiological and pathological implications. Clin Exp Hypertens A.1986;8: 781-785.
[90]Armanini D, Fiore C, Calo LA. Mononuclear leukocyte mineralocorticoid receptors. A possible link between aldosterone and atherosclerosis. Hypertension.2006;47:e4; author reply e4-5.
[91]Jaffe IZ, Mendelsohn ME. Angiotensin II and aldosterone regulate gene transcription via functional mineralocortocoid receptors in human coronary artery smooth muscle cells. Circ Res.2005;96:643-650.
[92]Fejes-Toth G, Naray-Fejes-Toth A. Early aldosterone-regulated genes in cardiomyocytes:clues to cardiac remodeling? Endocrinology.2007;148:1502-1510.
[93]Keidar S, Hayek T, Kaplan M, et al. Effect of eplerenone, a selective aldosterone blocker, on blood pressure, serum and macrophage oxidative stress, and atherosclerosis in apolipoprotein E-deficient mice. J Cardiovasc Pharmacol. 2003;41:955-963.
[94]Keidar S, Kaplan M, Pavlotzky E, et al. Aldosterone administration to mice stimulates macrophage NADPH oxidase and increases atherosclerosis development: a possible role for angiotensin-converting enzyme and the receptors for angiotensin II and aldosterone. Circulation.2004; 109:2213-2220.
[95]Michel F, Ambroisine ML, Duriez M, et al. Aldosterone enhances ischemia-induced neovascularization through angiotensin II-dependent pathway. Circulation. 2004;109:1933-1937.
[96]Ward MR, Kanellakis P, Ramsey D, et al. Eplerenone suppresses constrictive remodeling and collagen accumulation after angioplasty in porcine coronary arteries. Circulation.2001;104:467-472.
[97]Suzuki J, Iwai M, Mogi M, et al. Eplerenone with valsartan effectively reduces atherosclerotic lesion by attenuation of oxidative stress and inflammation. Arterioscler Thromb Vasc Biol.2006;26:917-921.
[98]Han SY, Kim CH, Kim HS, et al. Spironolactone prevents diabetic nephropathy through an anti-inflammatory mechanism in type 2 diabetic rats. J Am Soc Nephrol. 2006;17:1362-1372.
[99]Guo C, Martinez-Vasquez D, Mendez GP, et al. Mineralocorticoid receptor antagonist reduces renal injury in rodent models of types 1 and 2 diabetes mellitus. Endocrinology.2006;147:5363-5373.
[100]Harada E, Yoshimura M, Yasue H, et al. Aldosterone induces angiotensin-converting-enzyme gene expression in cultured neonatal rat cardiocytes. Circulation. 2001;104:137-139.
[101]Sugiyama T, Yoshimoto T, Tsuchiya K, et al. Aldosterone induces angiotensin converting enzyme gene expression via a JAK2-dependent pathway in rat endothelial cells. Endocrinology.2005; 146:3900-3906.
[102]Schiffrin EL, Franks DJ, Gutkowska J. Effect of aldosterone on vascular angiotensin II receptors in the rat. Can JPhysiol Pharmacol.1985;63:1522-1527.
[103]Ullian ME, Schelling JR, Linas SL. Aldosterone enhances angiotensin II receptor binding and inositol phosphate responses. Hypertension.1992;20:67-73.
[104]Mazak I, Fiebeler A, Muller DN, et al. Aldosterone potentiates angiotensin II-induced signaling in vascular smooth muscle cells. Circulation.2004; 109: 2792-2800.
[105]Robert V, Heymes C, Silvestre JS, et al. Angiotensin AT1 receptor subtype as a cardiac target of aldosterone:role in aldosterone-salt-induced fibrosis. Hypertension. 1999;33:981-986.
[106]Chun TY, Bloem LJ, Pratt JH. Aldosterone inhibits inducible nitric oxide synthase in neonatal rat cardiomyocytes. Endocrinology.2003;144:1712-1717.
[107]Ma LJ, Yang H, Gaspert A, et al. Transforming growth factor-beta-dependent and-independent pathways of induction of tubulointerstitial fibrosis in beta6(-/-) mice. Am J Pathol.2003;163:1261-1273.
[108]Dennler S, Itoh S, Vivien D, et al. Direct binding of Smad3 and Smad4 to critical
TGF beta-inducible elements in the promoter of human plasminogen activator inhibitor-type 1 gene. Embo J.1998; 17:3091-3100.
[109]Brown NJ, Kim KS, Chen YQ, et al. Synergistic effect of adrenal steroids and angiotensin II on plasminogen activator inhibitor-1 production. J Clin Endocrinol Metab.2000;85:336-344.
[110]Chun TY, Pratt JH. Aldosterone increases plasminogen activator inhibitor-1 synthesis in rat cardiomyocytes. Mol Cell Endocrinol.2005;239:55-61.
[111]Funder JW, Pearce PT, Smith R, et al. Vascular type I aldosterone binding sites are physiological mineralocorticoid receptors. Endocrinology.1989;125:2224-2226.
[112]Hatakeyama H, Inaba S, Takeda R, et al. llbeta-hydroxysteroid dehydrogenase in human vascular cells. Kidney Int.2000;57:1352-1357.
[113]Schiffrin EL, Gutkowska J, Genest J. Effect of angiotensin II and deoxycorticosterone infusion on vascular angiotensin II receptors in rats. Am J Physiol.1984;246:H608-614.
[114]Ullian ME, Hutchison FN, Hazen-Martin DJ, et al. Angiotensin II-aldosterone interactions on protein synthesis in vascular smooth muscle cells. Am J Physiol. 1993;264:C 1525-1531.
[115]Ullian ME, Fine JJ. Mechanisms of enhanced angiotensin II-stimulated signal transduction in vascular smooth muscle by aldosterone. J Cell Physiol.1994;161: 201-208.
[116]Min LJ, Mogi M, Li JM, et al. Aldosterone and angiotensin II synergistically induce mitogenic response in vascular smooth muscle cells. Circ Res.2005;97:434-442.
[117]Blaxall BC, Miano JM, Berk BC. Angiotensin II:a devious activator of mineralocorticoid receptor-dependent gene expression. Circ Res.2005;96:610-611.
[118]Fiebeler A, Schmidt F, Muller DN, et al. Mineralocorticoid receptor affects AP-1 and nuclear factor-kappab activation in angiotensin II-induced cardiac injury. Hypertension.2001;37:787-793.
[119]Nakamura Y, Suzuki S, Suzuki T, et al. MDM2:a novel mineralocorticoid-responsive gene involved in aldosterone-induced human vascular structural remodeling. Am JPathol.2006; 169:362-371.
[120]Ries S, Biederer C, Woods D, et al. Opposing effects of Ras on p53:transcriptional activation of mdm2 and induction of p19ARF. Cell.2000;103:321-330.
[121]Candeias MM, Malbert-Colas L, Powell DJ, et al. P53 mRNA controls p53 activity by managing Mdm2 functions. Nat Cell Biol.2008;10:1098-1105.
[122]Meulmeester E, Jochemsen AG p53:a guide to apoptosis. Curr Cancer Drug Targets.2008;8:87-97.
[123]Ihling C, Haendeler J, Menzel G, et al. Co-expression of p53 and MDM2 in human atherosclerosis:implications for the regulation of cellularity of atherosclerotic lesions. JPathol.1998;185:303-312.
[124]Honeck H, Gross V, Erdmann B, et al. Cytochrome P450-dependent renal arachidonic acid metabolism in desoxycorticosterone acetate-salt hypertensive mice. Hypertension.2000;36:610-616.
[125]Ishizawa K, Izawa Y, Ito H, et al. Aldosterone stimulates vascular smooth muscle cell proliferation via big mitogen-activated protein kinase 1 activation. Hypertension.2005;46:1046-1052.
[126]Grossmann C, Benesic A, Krug AW, et al. Human mineralocorticoid receptor expression renders cells responsive for nongenotropic aldosterone actions. Mol Endocrinol.2005;19:1697-1710.
[127]De Angelis N, Fiordaliso F, Latini R, et al. Appraisal of the role of angiotensin II and aldosterone in ventricular myocyte apoptosis in adult normotensive rat. J Mol Cell Cardiol.2002;34:1655-1665.
[128]Mathew JT, Patni H, Chaudhary AN, et al. Aldosterone induces mesangial cell apoptosis both in vivo and in vitro. Am JPhysiol Renal Physiol.2008;295:F73-81.
[129]Ben Rhouma K, Schimchowitsch S, Stoeckel ME, et al. [Implication of type II glucocorticoid receptors in aldosterone induced apoptosis of rat thymocytes]. Arch Physiol Biochem.1997; 105:216-224.
[130]Campbell SE, Janicki JS, Matsubara BB, et al. Myocardial fibrosis in the rat with mineralocorticoid excess. Prevention of scarring by amiloride. Am J Hypertens. 1993;6:487-495.
[131]Wei Y, Whaley-Connell AT, Habibi J, et al. Mineralocorticoid receptor antagonism attenuates vascular apoptosis and injury via rescuing protein kinase B activation. Hypertension.2009;53:158-165.
[132]Stowasser M. New perspectives on the role of aldosterone excess in cardiovascular disease. Clin Exp Pharmacol Physiol.2001;28:783-791.
[133]Ahokas RA, Sun Y, Bhattacharya SK, et al. Aldosteronism and a proinflammatory vascular phenotype:role of Mg2+, Ca2+, and H2O2 in peripheral blood mononuclear cells. Circulation.2005; 111:51-57.
[134]Bayorh MA, Ganafa AA, Emmett N, et al. Alterations in aldosterone and angiotensin II levels in salt-induced hypertension. Clin Exp Hypertens.2005;27: 355-367.
[135]Fan YY, Baba R, Nagai Y, et al. Augmentation of intrarenal angiotensin II levels in uninephrectomized aldosterone/salt-treated hypertensive rats; renoprotective effects of an ultrahigh dose of olmesartan. Hypertens Res.2006;29:169-178.
[2]Gordon RD, Stowasser M, Rutherford JC. Primary aldosteronism:are we diagnosing and operating on too few patients? World JSurg.2001;25:941-947.
[3]Young WF, Jr. Minireview:primary aldosteronism--changing concepts in diagnosis and treatment. Endocrinology.2003;144:2208-2213.
[4]Mulatero P, Stowasser M, Loh KC, et al. Increased diagnosis of primary aldosteronism, including surgically correctable forms, in centers from five continents. J Clin Endocrinol Metab.2004;89:1045-1050.
[5]Lumachi F, Ermani M, Basso SM, et al. Long-term results of adrenalectomy in patients with aldosterone-producing adenomas:multivariate analysis of factors affecting unresolved hypertension and review of the literature. Am Surg.2005;71:864-869.
[6]Meyer A, Brabant G, Behrend M. Long-term follow-up after adrenalectomy for primary aldosteronism. World J Surg.2005;29:155-159.
[7]Rossi G, Boscaro M, Ronconi V, et al. Aldosterone as a cardiovascular risk factor. Trends Endocrinol Metab.2005;16:104-107.
[8]Strauch B, Petrak O, Wichterle D, et al. Increased arterial wall stiffness in primary aldosteronism in comparison with essential hypertension. Am J Hypertens.2006;19: 909-914.
[9]Rossi GP, Bolognesi M, Rizzoni D, et al. Vascular remodeling and duration of hypertension predict outcome of adrenalectomy in primary aldosteronism patients. Hypertension.2008;51:1366-1371.
[10]Hatakeyama H, Miyamori I, Fujita T, et al. Vascular aldosterone. Biosynthesis and a link to angiotensin II-induced hypertrophy of vascular smooth muscle cells. J Biol Chem.1994;269:24316-24320.
[11]Funder JW, Pearce PT, Smith R, et al. Vascular type Ⅰ aldosterone binding sites are physiological mineralocorticoid receptors. Endocrinology.1989;125:2224-2226.
[12]Hatakeyama H, Inaba S, Takeda R, et al. llbeta-hydroxysteroid dehydrogenase in human vascular cells. Kidney Int.2000;57:1352-1357.
[13]Ishizawa K, Izawa Y, Ito H, et al. Aldosterone stimulates vascular smooth muscle cell proliferation via big mitogen-activated protein kinase 1 activation. Hypertension. 2005;46:1046-1052.
[14]Xiao F, Puddefoot JR, Barker S, et al. Mechanism for aldosterone potentiation of angiotensin II-stimulated rat arterial smooth muscle cell proliferation. Hypertension. 2004;44:340-345.
[15]Nakamura Y, Suzuki S, Suzuki T, et al. MDM2:a novel mineralocorticoid-responsive gene involved in aldosterone-induced human vascular structural remodeling. Am J Pathol.2006;169:362-371.
[16]王超,闫永吉,欧阳金芝等.鼠双微体-2基因在醛固酮增多症大鼠模型主动脉平滑肌中的表达.中华实验外科杂志.2009;26：630-632.
[17]Olson DC, Marechal V, Momand J, et al. Identification and characterization of multiple mdm-2 proteins and mdm-2-p53 protein complexes. Oncogene.1993;8: 2353-2360.
[18]Meulmeester E, Jochemsen AG p53:a guide to apoptosis. Curr Cancer Drug Targets. 2008;8:87-97.
[19]Patni H, Mathew JT, Luan L, et al. Aldosterone promotes proximal tubular cell apoptosis: role of oxidative stress. Am JPhysiol Renal Physiol.2007;293:F1065-1071.
[20]Mathew JT, Patni H, Chaudhary AN, et al. Aldosterone induces mesangial cell apoptosis both in vivo and in vitro. Am J Physiol Renal Physiol.2008;295:F73-81.
[21]Hayashi H, Kobara M, Abe M, et al. Aldosterone nongenomically produces NADPH oxidase-dependent reactive oxygen species and induces myocyte apoptosis. Hypertens Res.2008;31:363-375.
[22]Sharifi AM, Schiffrin EL. Apoptosis in aorta of deoxycorticosterone acetate-salt hypertensive rats:effect of endothelin receptor antagonism. J Hypertens.1997; 15: 1441-1448.
[23]Wei Y, Whaley-Connell AT, Habibi J, et al. Mineralocorticoid receptor antagonism attenuates vascular apoptosis and injury via rescuing protein kinase B activation. Hypertension.2009;53:158-165.
[24]Timpl R, Sasaki T, Kostka G, et al. Fibulins:a versatile family of extracellular matrix proteins. Nat Rev Mol Cell Biol.2003;4:479-489.
[25]Argraves WS, Greene LM, Cooley MA, et al. Fibulins:physiological and disease perspectives. EMBO Rep.2003;4:1127-1131.
[26]Loeys B, Van Maldergem L, Mortier G, et al. Homozygosity for a missense mutation in fibulin-5 (FBLN5) results in a severe form of cutis laxa. Hum Mol Genet.2002;11: 2113-2118.
[27]de Schepper S, Loeys B, de Paepe A, et al. Cutis laxa of the autosomal recessive type in a consanguineous family. Eur JDermatol.2003;13:529-533.
[28]Markova D, Zou Y, Ringpfeil F, et al. Genetic heterogeneity of cutis laxa:a heterozygous tandem duplication within the fibulin-5 (FBLN5) gene. Am J Hum Genet.2003;72:998-1004.
[29]Nakamura T, Lozano PR, Ikeda Y, et al. Fibulin-5/DANCE is essential for elastogenesis in vivo. Nature.2002;415:171-175.
[30]Yanagisawa H, Davis EC, Starcher BC, et al. Fibulin-5 is an elastin-binding protein essential for elastic fibre development in vivo. Nature.2002;415:168-171.
[31]Stone EM, Braun TA, Russell SR, et al. Missense variations in the fibulin 5 gene and age-related macular degeneration. NEngl J Med.2004;351:346-353.
[32]Sato Y, Sawada S, Nakanuma Y. Fibulin-5 is involved in phlebosclerosis of major portal vein branches associated with elastic fiber deposition in idiopathic portal hypertension. Hepatol Res.2008;38:166-173.
[33]Wang X, LeMaire SA, Chen L, et al. Decreased expression of fibulin-5 correlates with reduced elastin in thoracic aortic dissection. Surgery.2005;138:352-359.
[34]Spencer JA, Hacker SL, Davis EC, et al. Altered vascular remodeling in fibulin-5-deficient mice reveals a role of fibulin-5 in smooth muscle cell proliferation and migration. Proc Natl Acad Sci USA.2005;102:2946-2951.
[35]Schiemann WP, Blobe GC, Kalume DE, et al. Context-specific effects of fibulin-5 (DANCE/EVEC) on cell proliferation, motility, and invasion. Fibulin-5 is induced by transforming growth factor-beta and affects protein kinase cascades. J Biol Chem. 2002;277:27367-27377.
[36]Katsuta Y, Ogura Y, Iriyama S, et al. Fibulin-5 accelerates elastic fibre assembly in human skin fibroblasts. Exp Dermatol.2008;17:837-842.
[1]Ganguly A. Primary aldosteronism. N Engl J Med.1998;339:1828-1834.
[2]Young WF, Jr. Minireview:primary aldosteronism--changing concepts in diagnosis and treatment. Endocrinology.2003;144:2208-2213.
[3]Lumachi F, Ermani M, Basso SM, et al. Long-term results of adrenalectomy in patients with aldosterone-producing adenomas:multivariate analysis of factors affecting unresolved hypertension and review of the literature. Am Surg. 2005;71:864-869.
[4]Meyer A, Brabant G, Behrend M. Long-term follow-up after adrenalectomy for primary aldosteronism. World JSurg.2005;29:155-159.
[5]Ishizawa K, Izawa Y, Ito H, et al. Aldosterone stimulates vascular smooth muscle cell proliferation via big mitogen-activated protein kinase 1 activation. Hypertension.2005;46:1046-1052.
[6]Xiao F, Puddefoot JR, Barker S, et al. Mechanism for aldosterone potentiation of angiotensin II-stimulated rat arterial smooth muscle cell proliferation. Hypertension. 2004;44:340-345.
[7]Nakamura Y, Suzuki S, Suzuki T, et al. MDM2:a novel mineralocorticoid-responsive gene involved in aldosterone-induced human vascular structural remodeling. Am J Pathol.2006;169:362-371.
[8]王超,闫永吉,欧阳金芝等.鼠双微体-2基因在醛固酮增多症大鼠模型主动脉平滑肌中的表达.中化实验外科杂志.2009;26：630-632.
[9]Iwakuma T, Lozano G MDM2, an introduction. Mol Cancer Res.2003; 1:993-1000.
[10]Mulatero P, Stowasser M, Loh KC, et al. Increased diagnosis of primary aldosteronism, including surgically correctable forms, in centers from five continents. J Clin Endocrinol Metab.2004;89:1045-1050.
[11]Hatakeyama H, Miyamori I, Fujita T, et al. Vascular aldosterone. Biosynthesis and a link to angiotensin II-induced hypertrophy of vascular smooth muscle cells. J Biol Chem.1994;269:24316-24320.
[12]Funder JW, Pearce PT, Smith R, et al. Vascular type I aldosterone binding sites are physiological mineralocorticoid receptors. Endocrinology.1989;125:2224-2226.
[13]Hatakeyama H, Inaba S, Takeda R, et al. llbeta-hydroxysteroid dehydrogenase in human vascular cells. Kidney Int.2000;57:1352-1357.
[14]Lacolley P, Labat C, Pujol A, et al. Increased carotid wall elastic modulus and flbronectin in aldosterone-salt-treated rats:effects of eplerenone. Circulation. 2002;106:2848-2853.
[15]Park JB, Schiffrin EL. ET(A) receptor antagonist prevents blood pressure elevation and vascular remodeling in aldosterone-infused rats. Hypertension.2001;37:1444-1449.
[16]Iglarz M, Touyz RM, Viel EC, et al. Involvement of oxidative stress in the profibrotic action of aldosterone. Interaction wtih the renin-angiotension system. Am J Hypertens.2004;17:597-603.
[17]Meulmeester E, Jochemsen AG p53:a guide to apoptosis. Curr Cancer Drug Targets.2008;8:87-97.
[18]Martinet W, Knaapen MW, De Meyer GR, et al. Elevated levels of oxidative DNA damage and DNA repair enzymes in human atherosclerotic plaques. Circulation. 2002;106:927-932.
[19]Lopez-Candales A, Holmes DR, Liao S, et al. Decreased vascular smooth muscle cell density in medial degeneration of human abdominal aortic aneurysms. Am J Pathol.1997;150:993-1007.
[20]Brown NJ. Aldosterone and vascular inflammation. Hypertension.2008;51:161-167.
[21]Fritsche M, Haessler C, Brandner G Induction of nuclear accumulation of the tumor-suppressor protein p53 by DNA-damaging agents. Oncogene.1993;8:307-318.
[22]Chehab NH, Malikzay A, Stavridi ES, et al. Phosphorylation of Ser-20 mediates stabilization of human p53 in response to DNA damage. Proc Natl Acad Sci U S A. 1999;96:13777-13782.
[23]Vousden KH, Lu X. Live or let die:the cell's response to p53. Nat Rev Cancer. 2002;2:594-604.
[24]Ries S, Biederer C, Woods D, et al. Opposing effects of Ras on p53:transcriptional activation of mdm2 and induction of p19ARF. Cell.2000;103:321-330.
[25]Candeias MM, Malbert-Colas L, Powell DJ, et al. P53 mRNA controls p53 activity by managing Mdm2 functions. Nat Cell Biol.2008;10:1098-1105.
[26]Ihling C, Haendeler J, Menzel G, et al. Co-expression of p53 and MDM2 in human atherosclerosis:implications for the regulation of cellularity of atherosclerotic lesions. J Pathol. 1998;185:303-312.
[27]Fuller PJ, Young MJ. Mechanisms of mineralocorticoid action. Hypertension. 2005;46:1227-1235.
[1]Milliez P, Girerd X, Plouin PF, et al. Evidence for an increased rate of cardiovascular events in patients with primary aldosteronism. J Am Coll Cardiol. 2005;45:1243-1248.
[2]Amano T, Matsubara T, Izawa H, et al. Impact of plasma aldosterone levels for prediction of in-stent restenosis. Am J Cardiol.2006;97:785-788.
[3]Pitt B, Remme W, Zannad F, et al. Eplerenone, a selective aldosterone blocker, in patients with left ventricular dysfunction after myocardial infarction. N Engl J Med. 2003;348:1309-1321.
[4]Fuller PJ, Young MJ. Mechanisms of mineralocorticoid action. Hypertension. 2005;46:1227-1235.
[5]Hatakeyama H, Miyamori I, Fujita T, et al. Vascular aldosterone. Biosynthesis and a link to angiotensin II-induced hypertrophy of vascular smooth muscle cells. J Biol Chem.1994;269:24316-24320.
[6]Funder JW, Pearce PT, Smith R, et al. Vascular type I aldosterone binding sites are physiological mineralocorticoid receptors. Endocrinology.1989;125:2224-2226.
[7]Hatakeyama H, Inaba S, Takeda R, et al. llbeta-hydroxysteroid dehydrogenase in human vascular cells. Kidney Int.2000;57:1352-1357.
[8]Callera GE, Touyz RM, Tostes RC, et al. Aldosterone activates vascular p38MAP kinase and NADPH oxidase via c-Src. Hypertension.2005;45:773-779.
[9]Hirono Y, Yoshimoto T, Suzuki N, et al. Angiotensin II receptor type 1-mediated vascular oxidative stress and proinflammatory gene expression in aldosterone-induced hypertension:the possible role of local renin-angiotensin system. Endocrinology.2007;148:1688-1696.
[10]Iglarz M, Touyz RM, Viel EC, et al. Involvement of oxidative stress in the profibrotic action of aldosterone. Interaction wtih the renin-angiotension system. Am J Hypertens.2004;17:597-603.
[11]Lopez-Candales A, Holmes DR, Liao S, et al. Decreased vascular smooth muscle cell density in medial degeneration of human abdominal aortic aneurysms. Am J Pathol.1997;150:993-1007.
[12]von der Thusen JH, van Vlijmen BJ, Hoeben RC, et al. Induction of atherosclerotic plaque rupture in apolipoprotein E-/-mice after adenovirus-mediated transfer of p53. Circulation.2002;105:2064-2070.
[13]Korshunov VA, Berk BC. Smooth muscle apoptosis and vascular remodeling. Curr Opin Hematol.2008;15:250-254.
[14]Durand E, Scoazec A, Lafont A, et al. In vivo induction of endothelial apoptosis leads to vessel thrombosis and endothelial denudation:a clue to the understanding of the mechanisms of thrombotic plaque erosion. Circulation.2004;109:2503-2506.
[15]Patni H, Mathew JT, Luan L, et al. Aldosterone promotes proximal tubular cell apoptosis:role of oxidative stress. Am J Physiol Renal Physiol.2007;293: F1065-1071.
[16]Mathew JT, Patni H, Chaudhary AN, et al. Aldosterone induces mesangial cell apoptosis both in vivo and in vitro. Am J Physiol Renal Physiol.2008;295:F73-81.
[17]Hayashi H, Kobara M, Abe M, et al. Aldosterone nongenomically produces NADPH oxidase-dependent reactive oxygen species and induces myocyte apoptosis. Hypertens Res.2008;31:363-375.
[18]Sharifi AM, Schiffrin EL. Apoptosis in aorta of deoxycorticosterone acetate-salt hypertensive rats:effect of endothelin receptor antagonism. J Hypertens.1997;15: 1441-1448.
[19]Wei Y, Whaley-Connell AT, Habibi J, et al. Mineralocorticoid receptor antagonism attenuates vascular apoptosis and injury via rescuing protein kinase B activation. Hypertension.2009;53:158-165.
[20]Lumachi F, Ermani M, Basso SM, et al. Long-term results of adrenalectomy in patients with aldosterone-producing adenomas:multivariate analysis of factors affecting unresolved hypertension and review of the literature. Am Surg. 2005;71:864-869.
[21]Struthers A, Krum H, Williams GH. A comparison of the aldosterone-blocking agents eplerenone and spironolactone. Clin Cardiol.2008;31:153-158.
[22]Williams TA, Verhovez A, Milan A, et al. Protective effect of spironolactone on endothelial cell apoptosis. Endocrinology.2006;147:2496-2505.
[23]Li Y, Song YH, Mohler J, et al. ANG Ⅱ induces apoptosis of human vascular smooth muscle via extrinsic pathway involving inhibition of Akt phosphorylation and increased FasL expression. Am J Physiol Heart Circ Physiol.2006;290: H2116-2123.
[24]Li PF, Dietz R, von Harsdorf R. Differential effect of hydrogen peroxide and superoxide anion on apoptosis and proliferation of vascular smooth muscle cells. Circulation.1997;96:3602-3609.
[25]Mercer J, Mahmoudi M, Bennett M. DNA damage, p53, apoptosis and vascular disease. Mutat Res.2007;621:75-86.
[26]Kutuk O, Basaga H. Bcl-2 protein family:implications in vascular apoptosis and atherosclerosis. Apoptosis.2006; 11:1661-1675.
[27]Oltvai ZN, Milliman CL, Korsmeyer SJ. Bcl-2 heterodimerizes in vivo with a conserved homolog, Bax, that accelerates programmed cell death. Cell.1993;74: 609-619.
[1]Hueber AO, Evan GI. Traps to catch unwary oncogenes. Trends Genet. 1998;14:364-367.
[2]Mathew JT, Patni H, Chaudhary AN, et al. Aldosterone induces mesangial cell apoptosis both in vivo and in vitro. Am JPhysiol Renal Physiol.2008;295:F73-81.
[3]Hamet P. Proliferation and apoptosis of vascular smooth muscle in hypertension. Curr Opin Nephrol Hypertens.1995;4:1-7.
[4]Sharifi AM, Schiffrin EL. Apoptosis in aorta of deoxycorticosterone acetate-salt hypertensive rats:effect of endothelin receptor antagonism. J Hypertens.1997; 15: 1441-1448.
[5]Sharifi AM, Schiffrin EL. Apoptosis in vasculature of spontaneously hypertensive rats:effect of an angiotensin converting enzyme inhibitor and a calcium channel antagonist. Am J Hypertens.1998;11:1108-1116.
[6]Korshunov VA, Berk BC. Smooth muscle apoptosis and vascular remodeling. Curr Opin Hematol.2008;15:250-254.
[7]Rossig L, Dimmeler S, Zeiher AM. Apoptosis in the vascular wall and atherosclerosis. Basic Res Cardiol.2001;96:11-22.
[8]Durand E, Scoazec A, Lafont A, et al. In vivo induction of endothelial apoptosis leads to vessel thrombosis and endothelial denudation:a clue to the understanding of the mechanisms of thrombotic plaque erosion. Circulation.2004;109:2503-2506.
[9]Vousden KH, Lu X. Live or let die:the cell's response to p53. Nat Rev Cancer. 2002;2:594-604.
[10]Meulmeester E, Jochemsen AG p53:a guide to apoptosis. Curr Cancer Drug Targets.2008;8:87-97.
[11]Ihling C, Haendeler J, Menzel G, et al. Co-expression of p53 and MDM2 in human atherosclerosis:implications for the regulation of cellularity of atherosclerotic lesions. JPathol.1998;185:303-312.
[12]Thornborrow EC, Patel S, Mastropietro AE, et al. A conserved intronic response element mediates direct p53-dependent transcriptional activation of both the human
and murine bax genes. Oncogene.2002;21:990-999.
[13]Miyashita T, Harigai M, Hanada M, et al. Identification of a p53-dependent negative response element in the bcl-2 gene. Cancer Res.1994;54:3131-3135.
[14]Schnackenberg CG, Welch WJ, Wilcox CS. Normalization of blood pressure and renal vascular resistance in SHR with a membrane-permeable superoxide dismutase mimetic:role of nitric oxide. Hypertension.1998;32:59-64.
[15]Munzel T, Kurz S, Rajagopalan S, et al. Hydralazine prevents nitroglycerin tolerance by inhibiting activation of a membrane-bound NADH oxidase. A new action for an old drug.J Clin Invest.1996;98:1465-1470.
[16]Milliez P, Girerd X, Plouin PF, et al. Evidence for an increased rate of cardiovascular events in patients with primary aldosteronism. J Am Coll Cardiol. 2005;45:1243-1248.
[17]Lumachi F, Ermani M, Basso SM, et al. Long-term results of adrenalectomy in patients with aldosterone-producing adenomas:multivariate analysis of factors affecting unresolved hypertension and review of the literature. Am Surg. 2005;71:864-869.
[1]Mulatero P, Stowasser M, Loh KC, et al. Increased diagnosis of primary aldosteronism, including surgically correctable forms, in centers from five continents. J Clin Endocrinol Metab.2004;89:1045-1050.
[2]Lumachi F, Ermani M, Basso SM, et al. Long-term results of adrenalectomy in patients with aldosterone-producing adenomas:multivariate analysis of factors affecting unresolved hypertension and review of the literature. Am Surg. 2005;71:864-869.
[3]Fuller PJ, Young MJ. Mechanisms of mineralocorticoid action. Hypertension. 2005;46:1227-1235.
[4]Schiffrin EL. Effects of aldosterone on the vasculature. Hypertension.2006;47: 312-318.
[5]Ishizawa K, Izawa Y, Ito H, et al. Aldosterone stimulates vascular smooth muscle cell proliferation via big mitogen-activated protein kinase 1 activation. Hypertension.2005;46:1046-1052.
[6]Iglarz M, Touyz RM, Viel EC, et al. Involvement of oxidative stress in the profibrotic action of aldosterone. Interaction wtih the renin-angiotension system. Am J Hypertens.2004;17:597-603.
[7]Pu Q, Neves MF, Virdis A, et al. Endothelin antagonism on aldosterone-induced oxidative stress and vascular remodeling. Hypertension.2003;42:49-55.
[8]Lacolley P, Labat C, Pujol A, et al. Increased carotid wall elastic modulus and fibronectin in aldosterone-salt-treated rats:effects of eplerenone. Circulation. 2002; 106:2848-2853.
[9]Timpl R, Sasaki T, Kostka G, et al. Fibulins:a versatile family of extracellular matrix proteins. Nat Rev Mol Cell Biol.2003;4:479-489.
[10]Argraves WS, Greene LM, Cooley MA, et al. Fibulins:physiological and disease perspectives. EMBO Rep.2003;4:1127-1131.
[11]Loeys B, Van Maldergem L, Mortier G, et al. Homozygosity for a missense mutation in fibulin-5 (FBLN5) results in a severe form of cutis laxa. Hum Mol
Genet.2002;11:2113-2118.
[12]de Schepper S, Loeys B, de Paepe A, et al. Cutis laxa of the autosomal recessive type in a consanguineous family. Eur JDermatol.2003;13:529-533.
[13]Markova D, Zou Y, Ringpfeil F, et al. Genetic heterogeneity of cutis laxa:a heterozygous tandem duplication within the fibulin-5 (FBLN5) gene. Am J Hum Genet.2003;72:998-1004.
[14]Nakamura T, Lozano PR, Ikeda Y, et al. Fibulin-5/DANCE is essential for elastogenesis in vivo. Nature.2002;415:171-175.
[15]Yanagisawa H, Davis EC, Starcher BC, et al. Fibulin-5 is an elastin-binding protein essential for elastic fibre development in vivo. Nature.2002;415:168-171.
[16]Stone EM, Braun TA, Russell SR, et al. Missense variations in the fibulin 5 gene and age-related macular degeneration. N Engl J Med.2004;351:346-353.
[17]Sato Y, Sawada S, Nakanuma Y. Fibulin-5 is involved in phlebosclerosis of major portal vein branches associated with elastic fiber deposition in idiopathic portal hypertension. Hepatol Res.2008;38:166-173.
[18]Merklinger SL, Wagner RA, Spiekerkoetter E, et al. Increased fibulin-5 and elastin in S100A4/Mtsl mice with pulmonary hypertension. Ore Res.2005;97:596-604.
[19]Kuang PP, Goldstein RH, Liu Y, et al. Coordinate expression of fibulin-5/DANCE and elastin during lung injury repair. Am J Physiol Lung Cell Mol Physiol. 2003;285:L1147-1152.
[20]Wang X, LeMaire SA, Chen L, et al. Decreased expression of fibulin-5 correlates with reduced elastin in thoracic aortic dissection. Surgery.2005;138:352-359.
[21]Spencer JA, Hacker SL, Davis EC, et al. Altered vascular remodeling in fibulin-5-deficient mice reveals a role of fibulin-5 in smooth muscle cell proliferation and migration. Proc Natl Acad Sci USA.2005;102:2946-2951.
[22]Nakamura T, Ruiz-Lozano P, Lindner V, et al. DANCE, a novel secreted RGD protein expressed in developing, atherosclerotic, and balloon-injured arteries. J Biol Chem.1999;274:22476-22483.
[23]Schiemann WP, Blobe GC, Kalume DE, et al. Context-specific effects of fibulin-5 (DANCE/EVEC) on cell proliferation, motility, and invasion. Fibulin-5 is induced by transforming growth factor-beta and affects protein kinase cascades. J Biol Chem. 2002;277:27367-27377.
[24]Katsuta Y, Ogura Y, Iriyama S, et al. Fibulin-5 accelerates elastic fibre assembly in human skin fibroblasts. Exp Dermatol.2008;17:837-842.
[25]Funder J, Carey R, Fardella C, et al. Case detection, diagnosis, and treatment of patients with primary aldosteronism:an Endocrine Society clinical practice guideline. Eur J Endocrinol.2009.
[26]Safar ME. Systolic blood pressure, pulse pressure and arterial stiffness as cardiovascular risk factors. Curr Opin Nephrol Hypertens.2001;10:257-261.
[27]Seyrek N, Balal M, Karayaylali I, et al. Which parameter is more influential on the development of arteriosclerosis in hemodialysis patients? Ren Fail. 2003;25:1011-1018.
[28]Midwood KS, Schwarzbauer JE. Elastic fibers:building bridges between cells and their matrix. Curr Biol.2002;12:R279-281.
[29]Kielty CM, Sherratt MJ, Shuttleworth CA. Elastic fibres. J Cell Sci.2002;115: 2817-2828.
[30]Kowal RC, Richardson JA, Miano JM, et al. EVEC, a novel epidermal growth factor-like repeat-containing protein upregulated in embryonic and diseased adult vasculature. Circ Res.1999;84:1166-1176.
[31]Nguyen AD, Itoh S, Jeney V, et al. Fibulin-5 is a novel binding protein for extracellular superoxide dismutase. Circ Res.2004;95:1067-1074.
[32]Brown NJ. Aldosterone and vascular inflammation. Hypertension.2008;51:161-167.
[33]Zhao YD, Campbell AI, Robb M, et al. Protective role of angiopoietin-1 in experimental pulmonary hypertension. Circ Res.2003;92:984-991.
[34]Juknevicius I, Segal Y, Kren S, et al. Effect of aldosterone on renal transforming growth factor-beta. Am JPhysiol Renal Physiol.2004;286:F 1059-1062.
[35]Wakida N, Kitamura K, Tuyen DG, et al. Inhibition of prostasin-induced ENaC activities by PN-1 and regulation of PN-1 expression by TGF-betal and aldosterone. Kidney Int.2006;70:1432-1438.
[36]Sun GP, Kohno M, Guo P, et al. Involvements of Rho-kinase and TGF-beta pathways in aldosterone-induced renal injury. J Am Soc Nephrol.2006;17: 2193-2201.
[1]Trapp T, Holsboer F. Ligand-induced conformational changes in the mineralocorticoid receptor analyzed by protease mapping. Biochem Biophys Res Commun.1995;215:286-291.
[2]Fejes-Toth G, Pearce D, Naray-Fejes-Toth A. Subcellular localization of mineralocorticoid receptors in living cells:effects of receptor agonists and antagonists. Proc Natl Acad Sci USA.1998;95:2973-2978.
[3]Bhargava A, Fullerton MJ, Myles K, et al. The serum-and glucocorticoid-induced kinase is a physiological mediator of aldosterone action. Endocrinology.2001; 142: 1587-1594.
[4]Arriza JL, Weinberger C, Cerelli G, et al. Cloning of human mineralocorticoid receptor complementary DNA:structural and functional kinship with the glucocorticoid receptor. Science.1987;237:268-275.
[5]Chen SY, Bhargava A, Mastroberardino L, et al. Epithelial sodium channel regulated by aldosterone-induced protein sgk. Proc Natl Acad Sci U S A. 1999;96:2514-2519.
[6]Hatakeyama H, Miyamori I, Fujita T, et al. Vascular aldosterone. Biosynthesis and a link to angiotensin II-induced hypertrophy of vascular smooth muscle cells. J Biol Chem.1994;269:24316-24320.
[7]Takeda Y, Miyamori I, Yoneda T, et al. Regulation of aldosterone synthase in human vascular endothelial cells by angiotensin II and adrenocorticotropin. J Clin Endocrinol Metab.1996;81:2797-2800.
[8]Gomez-Sanchez CE, Zhou MY, Cozza EN, et al. Aldosterone biosynthesis in the rat brain. Endocrinology.1997;138:3369-3373.
[9]Silvestre JS, Robert V, Heymes C, et al. Myocardial production of aldosterone and corticosterone in the rat. Physiological regulation. J Biol Chem.1998;273: 4883-4891.
[10]Fuller PJ, Young MJ. Mechanisms of mineralocorticoid action. Hypertension. 2005;46:1227-1235.
[11]Losel RM, Falkenstein E, Feuring M, et al. Nongenomic steroid action: controversies, questions, and answers. Physiol Rev.2003;83:965-1016.
[12]Skott O, Uhrenholt TR, Schjerning J, et al. Rapid actions of aldosterone in vascular health and disease-friend or foe? Pharmacol Ther. 2006; 111:495-507.
[13]Pitt B, Zannad F, Remme WJ, et al. The effect of spironolactone on morbidity and mortality in patients with severe heart failure. Randomized Aldactone Evaluation Study Investigators. N Engl J Med.1999;341:709-717.
[14]Pitt B, Remme W, Zannad F, et al. Eplerenone, a selective aldosterone blocker, in patients with left ventricular dysfunction after myocardial infarction. N Engl J Med. 2003;348:1309-1321.
[15]Ramires FJ, Mansur A, Coelho O, et al. Effect of spironolactone on ventricular arrhythmias in congestive heart failure secondary to idiopathic dilated or to ischemic cardiomyopathy. Am J Cardiol.2000;85:1207-1211.
[16]Milliez P, Girerd X, Plouin PF, et al. Evidence for an increased rate of cardiovascular events in patients with primary aldosteronism. J Am Coll Cardiol. 2005;45:1243-1248.
[17]Rizzoni D, Porteri E, Castellano M, et al. Vascular hypertrophy and remodeling in secondary hypertension. Hypertension.1996;28:785-790.
[18]Safar ME, Cattan V, Lacolley P, et al. Aldosterone synthase gene polymorphism, stroke volume and age-related changes in aortic pulse wave velocity in subjects with hypertension. JHypertens.2005;23:1159-1166.
[19]Taddei S, Virdis A, Mattei P, et al. Vasodilation to acetylcholine in primary and secondary forms of human hypertension. Hypertension.1993;21:929-933.
[20]Nishizaka MK, Zaman MA, Green SA, et al. Impaired endothelium-dependent flow-mediated vasodilation in hypertensive subjects with hyperaldosteronism. Circulation.2004;109:2857-2861.
[21]Pu Q, Neves MF, Virdis A, et al. Endothelin antagonism on aldosterone-induced oxidative stress and vascular remodeling. Hypertension.2003;42:49-55.
[22]Arima S, Kohagura K, Xu HL, et al. Endothelium-derived nitric oxide modulates vascular action of aldosterone in renal arteriole. Hypertension.2004;43:352-357.
[23]Park JB, Schiffrin EL. ET(A) receptor antagonist prevents blood pressure elevation and vascular remodeling in aldosterone-infused rats. Hypertension.2001;37:1444-1449.
[24]Virdis A, Neves MF, Amiri F, et al. Spironolactone improves angiotensin-induced vascular changes and oxidative stress. Hypertension.2002;40:504-510.
[25]Romagni P, Rossi F, Guerrini L, et al. Aldosterone induces contraction of the resistance arteries in man. Atherosclerosis.2003; 166:345-349.
[26]Farquharson CA, Struthers AD. Aldosterone induces acute endothelial dysfunction in vivo in humans:evidence for an aldosterone-induced vasculopathy. Clin Sci (Lond).2002; 103:425-431.
[27]Davies JI, Band M, Morris A, et al. Spironolactone impairs endothelial function and heart rate variability in patients with type 2 diabetes. Diabetologia.2004;47: 1687-1694.
[28]Nishiyama A, Yao L, Nagai Y, et al. Possible contributions of reactive oxygen species and mitogen-activated protein kinase to renal injury in aldosterone/ salt-induced hypertensive rats. Hypertension.2004;43:841-848.
[29]Iglarz M, Touyz RM, Viel EC, et al. Involvement of oxidative stress in the profibrotic action of aldosterone. Interaction wtih the renin-angiotension system. Am J Hypertens.2004; 17:597-603.
[30]Blanco-Rivero J, Cachofeiro V, Lahera V, et al. Participation of prostacyclin in endothelial dysfunction induced by aldosterone in normotensive and hypertensive rats. Hypertension.2005;46:107-112.
[31]Nagata D, Takahashi M, Sawai K, et al. Molecular mechanism of the inhibitory effect of aldosterone on endothelial NO synthase activity. Hypertension. 2006;48:165-171.
[32]Vasquez-Vivar J, Kalyanaraman B, Martasek P, et al. Superoxide generation by endothelial nitric oxide synthase:the influence of cofactors. Proc Natl Acad Sci U S A.1998;95:9220-9225.
[33]Thai HM, Do BQ, Tran TD, et al. Aldosterone antagonism improves endothelial-dependent vasorelaxation in heart failure via upregulation of endothelial nitric oxide synthase production. J Card Fail.2006; 12:240-245.
[34]Calo LA, Zaghetto F, Pagnin E, et al. Effect of aldosterone and glycyrrhetinic acid on the protein expression of PAI-1 and p22(phox) in human mononuclear leukocytes. J Clin Endocrinol Metab.2004;89:1973-1976.
[35]Hirono Y, Yoshimoto T, Suzuki N, et al. Angiotensin Ⅱ receptor type 1-mediated vascular oxidative stress and proinflammatory gene expression in aldosterone-induced hypertension:the possible role of local renin-angiotensin system. Endocrinology.2007;148:1688-1696.
[36]Sanz-Rosa D, Oubina MP, Cediel E, et al. Eplerenone reduces oxidative stress and enhances eNOS in SHR:vascular functional and structural consequences. Antioxid Redox Signal.2005;7:1294-1301.
[37]Lariviere R, Thibault G, Schiffrin EL. Increased endothelin-1 content in blood vessels of deoxycorticosterone acetate-salt hypertensive but not in spontaneously hypertensive rats. Hypertension.1993;21:294-300.
[38]Arima S, Kohagura K, Xu HL, et al. Nongenomic vascular action of aldosterone in the glomerular microcirculation. J Am Soc Nephrol.2003;14:2255-2263.
[39]Fujita M, Minamino T, Asanuma H, et al. Aldosterone nongenomically worsens ischemia via protein kinase C-dependent pathways in hypoperfused canine hearts. Hypertension.2005;46:113-117.
[40]Liu SL, Schmuck S, Chorazcyzewski JZ, et al. Aldosterone regulates vascular reactivity:short-term effects mediated by phosphatidylinositol 3-kinase-dependent nitric oxide synthase activation. Circulation.2003; 108:2400-2406.
[41]Oberleithner H, Riethmuller C, Ludwig T, et al. Aldosterone remodels human endothelium. Acta Physiol (Oxf).2006;187:305-312.
[42]Petry A, Djordjevic T, Weitnauer M, et al. NOX2 and NOX4 mediate proliferative response in endothelial cells. Antioxid Redox Signal.2006;8:1473-1484.
[43]Paravicini TM, Touyz RM. Redox signaling in hypertension. Cardiovasc Res. 2006;71:247-258.
[44]Sun Y, Zhang J, Lu L, et al. Aldosterone-induced inflammation in the rat heart:role of oxidative stress. Am JPathol.2002; 161:1773-1781.
[45]Shibata S, Nagase M, Yoshida S, et al. Podocyte as the target for aldosterone:roles of oxidative stress and Sgk1. Hypertension.2007;49:355-364.
[46]Johar S, Cave AC, Narayanapanicker A, et al. Aldosterone mediates angiotensin Ⅱ-induced interstitial cardiac fibrosis via a Nox2-containing NADPH oxidase. Faseb J.2006;20:1546-1548.
[47]Stas S, Whaley-Connell A, Habibi J, et al. Mineralocorticoid receptor blockade attenuates chronic overexpression of the renin-angiotensin-aldosterone system stimulation of reduced nicotinamide adenine dinucleotide phosphate oxidase and cardiac remodeling. Endocrinology.2007; 148:3773-3780.
[48]Callera GE, Touyz RM, Tostes RC, et al. Aldosterone activates vascular p38MAP kinase and NADPH oxidase via c-Src. Hypertension.2005;45:773-779.
[49]Patni H, Mathew JT, Luan L, et al. Aldosterone promotes proximal tubular cell apoptosis:role of oxidative stress. Am J Physiol Renal Physiol.2007;293: F1065-1071.
[50]Leopold JA, Dam A, Maron BA, et al. Aldosterone impairs vascular reactivity by decreasing glucose-6-phosphate dehydrogenase activity. Nat Med.2007;13:189-197.
[51]Park YM, Park MY, Suh YL, et al. NAD(P)H oxidase inhibitor prevents blood pressure elevation and cardiovascular hypertrophy in aldosterone-infused rats. Biochem Biophys Res Commun.2004;313:812-817.
[52]Li L, Fink GD, Watts SW, et al. Endothelin-1 increases vascular superoxide via endothelin(A)-NADPH oxidase pathway in low-renin hypertension. Circulation. 2003;107:1053-1058.
[53]Callera GE, Montezano AC, Touyz RM, et al. ETA receptor mediates altered leukocyte-endothelial cell interaction and adhesion molecules expression in DOCA-salt rats. Hypertension.2004;43:872-879.
[54]Wong S, Brennan FE, Young MJ, et al. A direct effect of aldosterone on endothelin-1 gene expression in vivo. Endocrinology.2007; 148:1511-1517.
[55]Callera GE, Tostes RC, Yogi A, et al. Endothelin-1-induced oxidative stress in DOCA-salt hypertension involves NADPH-oxidase-independent mechanisms. Clin Sci (Lond).2006; 110:243-253.
[56]Hao L, Nishimura T, Wo H, et al. Vascular responses to alphal-adrenergic receptors in small rat mesenteric arteries depend on mitochondrial reactive oxygen species. Arterioscler Thromb Vasc Biol.2006;26:819-825.
[57]Ebata S, Muto S, Okada K, et al. Aldosterone activates Na+/H+ exchange in vascular smooth muscle cells by nongenomic and genomic mechanisms. Kidney Int. 1999;56:1400-1412.
[58]Rocha R, Chander PN, Zuckerman A, et al. Role of aldosterone in renal vascular injury in stroke-prone hypertensive rats. Hypertension.1999;33:232-237.
[59]Rocha R, Martin-Berger CL, Yang P, et al. Selective aldosterone blockade prevents angiotensin II/salt-induced vascular inflammation in the rat heart. Endocrinology. 2002; 143:4828-4836.
[60]Tostes RC, Touyz RM, He G, et al. Contribution of endothelin-1 to renal activator protein-1 activation and macrophage infiltration in aldosterone-induced hypertension. Clin Sci (Lond).2002; 103 Suppl 48:25S-30S.
[61]Young MJ, Moussa L, Dilley R, et al. Early inflammatory responses in experimental cardiac hypertrophy and fibrosis:effects of 11 beta-hydroxysteroid dehydrogenase inactivation. Endocrinology.2003;144:1121-1125.
[62]Rocha R, Rudolph AE, Frierdich GE, et al. Aldosterone induces a vascular inflammatory phenotype in the rat heart. Am J Physiol Heart Circ Physiol. 2002;283:H1802-1810.
[63]Young M, Funder JW. Eplerenone, but not steroid withdrawal, reverses cardiac fibrosis in deoxycorticosterone/salt-treated rats. Endocrinology.2004; 145:3153-3157.
[64]Pickering TG Stress, inflammation, and hypertension. J Clin Hypertens (Greenwich).2007;9:567-571.
[65]Irita J, Okura T, Manabe S, et al. Plasma osteopontin levels are higher in patients with primary aldosteronism than in patients with essential hypertension. Am J Hypertens.2006; 19:293-297.
[66]Scatena M, Liaw L, Giachelli CM. Osteopontin:a multifunctional molecule regulating chronic inflammation and vascular disease. Arterioscler Thromb Vasc Biol.2007;27:2302-2309.
[67]Clapp BR, Hirschfield GM, Storry C, et al. Inflammation and endothelial function: direct vascular effects of human C-reactive protein on nitric oxide bioavailability. Circulation.2005; 111:1530-1536.
[68]Luther JM, Gainer JV, Murphey LJ, et al. Angiotensin II induces interleukin-6 in humans through a mineralocorticoid receptor-dependent mechanism. Hypertension. 2006;48:1050-1057.
[69]Sawathiparnich P, Kumar S, Vaughan DE, et al. Spironolactone abolishes the relationship between aldosterone and plasminogen activator inhibitor-1 in humans. J Clin Endocrinol Metab.2002;87:448-452.
[70]Sawathiparnich P, Murphey LJ, Kumar S, et al. Effect of combined ATI receptor and aldosterone receptor antagonism on plasminogen activator inhibitor-1. J Clin Endocrinol Metab.2003;88:3867-3873.
[71]Ma J, Albornoz F, Yu C, et al. Differing effects of mineralocorticoid receptor-dependent and-independent potassium-sparing diuretics on fibrinolytic balance. Hypertension.2005;46:313-320.
[72]Gils A, Declerck PJ. Plasminogen activator inhibitor-1. Curr Med Chem. 2004; 11:2323-2334.
[73]Stefansson S, Lawrence DA. Old dogs and new tricks:proteases, inhibitors, and cell migration. Sci STKE.2003;2003:pe24.
[74]Brown NJ, Agirbasli MA, Williams GH, et al. Effect of activation and inhibition of the renin-angiotensin system on plasma PAI-1. Hypertension.1998;32:965-971.
[75]Takebayashi K, Matsumoto S, Aso Y, et al. Aldosterone blockade attenuates urinary monocyte chemoattractant protein-1 and oxidative stress in patients with type 2 diabetes complicated by diabetic nephropathy. J Clin Endocrinol Metab. 2006;91:2214-2217.
[76]Matsumoto S, Takebayashi K, Aso Y. The effect of spironolactone on circulating adipocytokines in patients with type 2 diabetes mellitus complicated by diabetic nephropathy. Metabolism.2006;55:1645-1652.
[77]Kasifoglu T, Yalcin AU. The effects of thiazide and thiazide-potassium sparing diuretics on fibrinolytic system parameters. Anadolu Kardiyol Derg.2006;6: 143-147.
[78]Ingelsson E, Pencina MJ, Tofler GH, et al. Multimarker approach to evaluate the incidence of the metabolic syndrome and longitudinal changes in metabolic risk factors:the Framingham Offspring Study. Circulation.2007; 116:984-992.
[79]Godfrey V, Farquharson CA, Macdonald JE, et al. Effect of spironolactone on C-reactive protein levels in patients with heart disease. Int J Cardiol.2007; 117: 282-284.
[80]Benetos A, Lacolley P, Safar ME. Prevention of aortic fibrosis by spironolactone in spontaneously hypertensive rats. Arterioscler Thromb Vasc Biol.1997; 17:1152-1156.
[81]Lacolley P, Labat C, Pujol A, et al. Increased carotid wall elastic modulus and fibronectin in aldosterone-salt-treated rats:effects of eplerenone. Circulation. 2002;106:2848-2853.
[82]Neves MF, Amiri F, Virdis A, et al. Role of aldosterone in angiotensin II-induced cardiac and aortic inflammation, fibrosis, and hypertrophy. Can J Physiol Pharmacol.2005;83:999-1006.
[83]Blasi ER, Rocha R, Rudolph AE, et al. Aldosterone/salt induces renal inflammation and fibrosis in hypertensive rats. Kidney Int.2003;63:1791-1800.
[84]Fiebeler A, Nussberger J, Shagdarsuren E, et al. Aldosterone synthase inhibitor ameliorates angiotensin II-induced organ damage. Circulation.2005; 111:3087-3094.
[85]Lam EY, Funder JW, Nikolic-Paterson DJ, et al. Mineralocorticoid receptor blockade but not steroid withdrawal reverses renal fibrosis in deoxycorticosterone/ salt rats. Endocrinology.2006;147:3623-3629.
[86]Guzik TJ, Hoch NE, Brown KA, et al. Role of the T cell in the genesis of angiotensin II induced hypertension and vascular dysfunction. J Exp Med. 2007;204:2449-2460.
[87]Sanz-Rosa D, Cediel E, de las Heras N, et al. Participation of aldosterone in the vascular inflammatory response of spontaneously hypertensive rats:role of the NFkappaB/IkappaB system. JHypertens.2005;23:1167-1172.
[88]de Winther MP, Kanters E, Kraal G, et al. Nuclear factor kappaB signaling in atherogenesis. Arterioscler Thromb Vasc Biol.2005;25:904-914.
[89]Armanini D, Kuhnle U, Witzgall H, et al. The determination of mineralocorticoid receptors in human mononuclear leukocytes from patients with mineralocorticoid excess:physiological and pathological implications. Clin Exp Hypertens A.1986;8: 781-785.
[90]Armanini D, Fiore C, Calo LA. Mononuclear leukocyte mineralocorticoid receptors. A possible link between aldosterone and atherosclerosis. Hypertension.2006;47:e4; author reply e4-5.
[91]Jaffe IZ, Mendelsohn ME. Angiotensin II and aldosterone regulate gene transcription via functional mineralocortocoid receptors in human coronary artery smooth muscle cells. Circ Res.2005;96:643-650.
[92]Fejes-Toth G, Naray-Fejes-Toth A. Early aldosterone-regulated genes in cardiomyocytes:clues to cardiac remodeling? Endocrinology.2007;148:1502-1510.
[93]Keidar S, Hayek T, Kaplan M, et al. Effect of eplerenone, a selective aldosterone blocker, on blood pressure, serum and macrophage oxidative stress, and atherosclerosis in apolipoprotein E-deficient mice. J Cardiovasc Pharmacol. 2003;41:955-963.
[94]Keidar S, Kaplan M, Pavlotzky E, et al. Aldosterone administration to mice stimulates macrophage NADPH oxidase and increases atherosclerosis development: a possible role for angiotensin-converting enzyme and the receptors for angiotensin II and aldosterone. Circulation.2004; 109:2213-2220.
[95]Michel F, Ambroisine ML, Duriez M, et al. Aldosterone enhances ischemia-induced neovascularization through angiotensin II-dependent pathway. Circulation. 2004;109:1933-1937.
[96]Ward MR, Kanellakis P, Ramsey D, et al. Eplerenone suppresses constrictive remodeling and collagen accumulation after angioplasty in porcine coronary arteries. Circulation.2001;104:467-472.
[97]Suzuki J, Iwai M, Mogi M, et al. Eplerenone with valsartan effectively reduces atherosclerotic lesion by attenuation of oxidative stress and inflammation. Arterioscler Thromb Vasc Biol.2006;26:917-921.
[98]Han SY, Kim CH, Kim HS, et al. Spironolactone prevents diabetic nephropathy through an anti-inflammatory mechanism in type 2 diabetic rats. J Am Soc Nephrol. 2006;17:1362-1372.
[99]Guo C, Martinez-Vasquez D, Mendez GP, et al. Mineralocorticoid receptor antagonist reduces renal injury in rodent models of types 1 and 2 diabetes mellitus. Endocrinology.2006;147:5363-5373.
[100]Harada E, Yoshimura M, Yasue H, et al. Aldosterone induces angiotensin-converting-enzyme gene expression in cultured neonatal rat cardiocytes. Circulation. 2001;104:137-139.
[101]Sugiyama T, Yoshimoto T, Tsuchiya K, et al. Aldosterone induces angiotensin converting enzyme gene expression via a JAK2-dependent pathway in rat endothelial cells. Endocrinology.2005; 146:3900-3906.
[102]Schiffrin EL, Franks DJ, Gutkowska J. Effect of aldosterone on vascular angiotensin II receptors in the rat. Can JPhysiol Pharmacol.1985;63:1522-1527.
[103]Ullian ME, Schelling JR, Linas SL. Aldosterone enhances angiotensin II receptor binding and inositol phosphate responses. Hypertension.1992;20:67-73.
[104]Mazak I, Fiebeler A, Muller DN, et al. Aldosterone potentiates angiotensin II-induced signaling in vascular smooth muscle cells. Circulation.2004; 109: 2792-2800.
[105]Robert V, Heymes C, Silvestre JS, et al. Angiotensin AT1 receptor subtype as a cardiac target of aldosterone:role in aldosterone-salt-induced fibrosis. Hypertension. 1999;33:981-986.
[106]Chun TY, Bloem LJ, Pratt JH. Aldosterone inhibits inducible nitric oxide synthase in neonatal rat cardiomyocytes. Endocrinology.2003;144:1712-1717.
[107]Ma LJ, Yang H, Gaspert A, et al. Transforming growth factor-beta-dependent and-independent pathways of induction of tubulointerstitial fibrosis in beta6(-/-) mice. Am J Pathol.2003;163:1261-1273.
[108]Dennler S, Itoh S, Vivien D, et al. Direct binding of Smad3 and Smad4 to critical
TGF beta-inducible elements in the promoter of human plasminogen activator inhibitor-type 1 gene. Embo J.1998; 17:3091-3100.
[109]Brown NJ, Kim KS, Chen YQ, et al. Synergistic effect of adrenal steroids and angiotensin II on plasminogen activator inhibitor-1 production. J Clin Endocrinol Metab.2000;85:336-344.
[110]Chun TY, Pratt JH. Aldosterone increases plasminogen activator inhibitor-1 synthesis in rat cardiomyocytes. Mol Cell Endocrinol.2005;239:55-61.
[111]Funder JW, Pearce PT, Smith R, et al. Vascular type I aldosterone binding sites are physiological mineralocorticoid receptors. Endocrinology.1989;125:2224-2226.
[112]Hatakeyama H, Inaba S, Takeda R, et al. llbeta-hydroxysteroid dehydrogenase in human vascular cells. Kidney Int.2000;57:1352-1357.
[113]Schiffrin EL, Gutkowska J, Genest J. Effect of angiotensin II and deoxycorticosterone infusion on vascular angiotensin II receptors in rats. Am J Physiol.1984;246:H608-614.
[114]Ullian ME, Hutchison FN, Hazen-Martin DJ, et al. Angiotensin II-aldosterone interactions on protein synthesis in vascular smooth muscle cells. Am J Physiol. 1993;264:C 1525-1531.
[115]Ullian ME, Fine JJ. Mechanisms of enhanced angiotensin II-stimulated signal transduction in vascular smooth muscle by aldosterone. J Cell Physiol.1994;161: 201-208.
[116]Min LJ, Mogi M, Li JM, et al. Aldosterone and angiotensin II synergistically induce mitogenic response in vascular smooth muscle cells. Circ Res.2005;97:434-442.
[117]Blaxall BC, Miano JM, Berk BC. Angiotensin II:a devious activator of mineralocorticoid receptor-dependent gene expression. Circ Res.2005;96:610-611.
[118]Fiebeler A, Schmidt F, Muller DN, et al. Mineralocorticoid receptor affects AP-1 and nuclear factor-kappab activation in angiotensin II-induced cardiac injury. Hypertension.2001;37:787-793.
[119]Nakamura Y, Suzuki S, Suzuki T, et al. MDM2:a novel mineralocorticoid-responsive gene involved in aldosterone-induced human vascular structural remodeling. Am JPathol.2006; 169:362-371.
[120]Ries S, Biederer C, Woods D, et al. Opposing effects of Ras on p53:transcriptional activation of mdm2 and induction of p19ARF. Cell.2000;103:321-330.
[121]Candeias MM, Malbert-Colas L, Powell DJ, et al. P53 mRNA controls p53 activity by managing Mdm2 functions. Nat Cell Biol.2008;10:1098-1105.
[122]Meulmeester E, Jochemsen AG p53:a guide to apoptosis. Curr Cancer Drug Targets.2008;8:87-97.
[123]Ihling C, Haendeler J, Menzel G, et al. Co-expression of p53 and MDM2 in human atherosclerosis:implications for the regulation of cellularity of atherosclerotic lesions. JPathol.1998;185:303-312.
[124]Honeck H, Gross V, Erdmann B, et al. Cytochrome P450-dependent renal arachidonic acid metabolism in desoxycorticosterone acetate-salt hypertensive mice. Hypertension.2000;36:610-616.
[125]Ishizawa K, Izawa Y, Ito H, et al. Aldosterone stimulates vascular smooth muscle cell proliferation via big mitogen-activated protein kinase 1 activation. Hypertension.2005;46:1046-1052.
[126]Grossmann C, Benesic A, Krug AW, et al. Human mineralocorticoid receptor expression renders cells responsive for nongenotropic aldosterone actions. Mol Endocrinol.2005;19:1697-1710.
[127]De Angelis N, Fiordaliso F, Latini R, et al. Appraisal of the role of angiotensin II and aldosterone in ventricular myocyte apoptosis in adult normotensive rat. J Mol Cell Cardiol.2002;34:1655-1665.
[128]Mathew JT, Patni H, Chaudhary AN, et al. Aldosterone induces mesangial cell apoptosis both in vivo and in vitro. Am JPhysiol Renal Physiol.2008;295:F73-81.
[129]Ben Rhouma K, Schimchowitsch S, Stoeckel ME, et al. [Implication of type II glucocorticoid receptors in aldosterone induced apoptosis of rat thymocytes]. Arch Physiol Biochem.1997; 105:216-224.
[130]Campbell SE, Janicki JS, Matsubara BB, et al. Myocardial fibrosis in the rat with mineralocorticoid excess. Prevention of scarring by amiloride. Am J Hypertens. 1993;6:487-495.
[131]Wei Y, Whaley-Connell AT, Habibi J, et al. Mineralocorticoid receptor antagonism attenuates vascular apoptosis and injury via rescuing protein kinase B activation. Hypertension.2009;53:158-165.
[132]Stowasser M. New perspectives on the role of aldosterone excess in cardiovascular disease. Clin Exp Pharmacol Physiol.2001;28:783-791.
[133]Ahokas RA, Sun Y, Bhattacharya SK, et al. Aldosteronism and a proinflammatory vascular phenotype:role of Mg2+, Ca2+, and H2O2 in peripheral blood mononuclear cells. Circulation.2005; 111:51-57.
[134]Bayorh MA, Ganafa AA, Emmett N, et al. Alterations in aldosterone and angiotensin II levels in salt-induced hypertension. Clin Exp Hypertens.2005;27: 355-367.
[135]Fan YY, Baba R, Nagai Y, et al. Augmentation of intrarenal angiotensin II levels in uninephrectomized aldosterone/salt-treated hypertensive rats; renoprotective effects of an ultrahigh dose of olmesartan. Hypertens Res.2006;29:169-178.
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