SPae抑制炎症反应和细胞泡沫化的作用及其机制研究暨支架相关Meta分析
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摘要
背景
血管的慢性炎症贯穿整个动脉粥样硬化(atherosclerosis, AS)的发生发展过程。特别是在动脉粥样硬化早期阶段,内皮功能障碍发挥了主要的作用。在多种致病因素的作用下,血管内皮细胞活化,粘附分子、致炎细胞因子及化学趋化因子的表达增加,协助炎症细胞浸润,造成内皮功能障碍、氧化应激增加,细胞凋亡、脂质沉积,最终导致动脉硬化的发生。
转录因子κB (NF-κB)活化与动脉粥样硬化的炎症反应发生和发展密切相关。NF-κB是由P50, P52, P65, Re1B和c-Rel等五种分子组成的同源或异源二聚体并参与调控体内病理生理如免疫、炎症、增殖等过程。在细胞处于正常状态时,NF-κB的组成成分限制在胞浆中,而当细胞受到外界刺激后,NF-κB抑制因子(IκBs)被其上游的IκB激酶(IKK)复合物激活,发生磷酸化,随后被泛素化及蛋白酶体降解,最终导致NF-κB(主要是P65/P50二聚体形式)的释放并由胞浆转位至胞核,参与调控目的基因的转录及表达。
在动脉粥样硬化形成的过程中,氧化应激发挥着重大作用。氧化应激是过量的活性氧与内源性清除活性氧的抗氧化系统间失去平衡。活性氧影响血管内皮的很多功能,如介导血管内皮细胞和平滑肌细胞生长、凋亡和存活等表型调节,内皮依赖的血管扩张,参与血管壁缺失一氧化氮(NO)生物活性而损伤,增加单核细胞粘附和在血管生成中起作用。
丹皮酚磺酸钠(Sodium Paeonolsilate, SPae)是从中药牡丹皮中分离提取的丹皮酚经磺化、成盐形成的一种新的化合物,具有抗炎、止痛、抗肿瘤、抗脂质过氧化、免疫调节等多重作用,近年有研究表明其具有抗动脉粥样硬化作用,但具体作用机制仍不清楚。因此,我们观察了丹皮酚磺酸钠对血管炎症影响,并探讨其可能的作用机制。
目的
1.研究丹皮酚磺酸钠对肿瘤坏死因子α (TNF-a)诱导的单核细胞粘附分子、致炎因子及化学趋化因子受体表达的影响。
2.研究丹皮酚磺酸钠对TNF-α诱导内皮细胞的NF-κB活性、氧化应激的影响及可能的机制。
方法
1)人动脉内皮细胞1human aortic endothelial cells, HAECs)的培养
人动脉内皮细胞(himan aortic endothelial cells, HAECs)培养在含有10%FBS的ECM培养基中,置于5%C02,37℃培养箱中培养,每三天换一次液,并根据需要进行传代和铺板。
2)细胞模型的建立
HAECs与5,10和20ng/ml的fNF-α共孵育24h, Western Blot检测内皮细胞ICAM-1和VCAM-1的表达。
3)单核细胞粘附实验
用终浓度为5μmol/L的钙黄绿素-AM (calcein-AM)标记的THP-1细胞接种在HAECs上。避光条件下,37℃共同孵育2h。用PBS轻轻清洗细胞2-3次,去除未粘附的单核细胞,加入2mlPBS,于激光共聚焦显微镜下观察,激发波长485nm,发射波长530nm。
4) ROS检测
按照ROS试剂盒操作说明,运用二氯二氢荧光素-乙酰乙酸酯(DCFH-DA)探针检测丹皮酚磺酸钠处理后,细胞内超氧化物的释放情况。
5) NO、超氧化物歧化酶(SOD)、乳酸脱氢酶(LDH)检测
按照NO、SOD、LDH试剂盒操作测定一氧化氮、超氧化物歧化酶、乳酸脱氢酶。
6) Western blot蛋白检测
检测丹皮酚磺酸钠处理后,细胞间粘附分子-1(ICAM-1)、血管细胞粘附分子-1(VCAM-1)的表达,磷酸化内皮型一氧化氮合酶(p-eNOS),以及NF-κB.p-IKKβ活性。
7)小鼠在体炎症模型的建立
本实验采用30μg/kg TNF-α经腹腔注射(i.p.)48h建立小鼠在体炎症模型。
8)血清中ICAM-1、VCAM-1、白介素8(IL-8)、单核细胞趋化蛋白1(MCP-1)检测
取动脉血,按照ELISA试剂盒说明,检测血浆中ICAM-1、VCAM-1、IL-8、MCP-1水平。
免疫组化
麻醉小鼠,取出胸主动脉,蔗糖梯度溶液中脱水,石蜡包埋组织,石蜡切片机切片,主动脉按冠状切面切取厚度为4μm的组织切片,-80℃保存。按照操作步骤进行ICAM-1和VCAM-1的组织染色。
结果
1.丹皮酚磺酸钠能够抑制TNF-α诱导的ICAM-1和VCAM-1的表达,减少活性氧簇(ROS)释放,增加NO、SOD的生成。
2.丹皮酚磺酸钠上调TNF-α诱导的内皮细胞eNOS磷酸化水平和降低NF-κB活性及p-IKKβ的表达。
3.丹皮酚磺酸钠在体模型上抑制TNF-α诱导的血管炎症反应。
结论
丹皮酚磺酸钠能够抑制TNF-α诱导的ICAM-1和VCAM-1的表达,减少活性氧簇(ROS)释放,增加NO、SOD的生成,降低血管炎症反应,维持内皮细胞正常功能。
背景
巨噬细胞泡沫化和炎症因子在动脉粥样硬化(AS)发生发展中扮演了重要角色。内皮功能障碍被是AS的始动因素,而脂质代谢紊乱是AS发生的关键环节。氧化应激一方面引起内皮损伤,另一方面修饰LDL成氧化低密度脂蛋白(ox-LDL)。 ox-LDL-一方面加剧内皮炎症,另一方面加速巨噬细胞形成泡沫细胞。而泡沫细胞凋亡或坏死后,将细胞内的脂质释放出来,形成条纹状粥样硬化斑块。由此可见,泡沫细胞的形成在动脉粥样硬化的发生、发展中同样扮演着一个十分重要的角色。
从中药牡丹皮中分离提取的丹皮酚经磺化、成盐形成的丹皮酚磺酸化钠(Spae),具有抗炎、止痛、抗肿瘤、抗脂质过氧化、免疫调节等多重作用,我们上一章节已经发现SPae具有抵抗肿瘤坏死因子α(TNF-a)诱导的氧化应激效应和抗血管炎症。同时,众多研究证明细胞泡沫化形成也伴随着炎症的产生和氧化应激的的继续,我们进一步观察SPae是否抑制ox-LDL诱导的巨噬细胞泡沫化和动脉粥样硬化形成。
为此,本课题从以下三个方面在细胞模型和在体模型探讨SPae对ox-LDL诱导的巨噬细胞泡沫化和动脉粥样硬化形成的影响。1.建立巨噬细胞泡沫化细胞模型,并观察SPae对巨噬细胞泡沫化吞噬ox-LDL能力的影响,以及对清道夫受体CD36、清道夫受体A (SRA)和ATP结合盒转运蛋白A1(ABCA1)的表达的影响；2.采用apoE-/-小鼠动脉硬化模型,研究SPae对AS的治疗作用；3.从分子水平探讨其潜在的作用机制。
目的：
1)研究APse对巨噬细胞泡沫化形成的影响
2)探讨载体模型中,SPae对AS早期斑块发展的影响。
方法：
1)巨噬细胞泡沫化模型建立与鉴定
THP-1细胞经10Ong/ml丙二醇甲醚醋酸酯(PMA)诱导分化24h后,80μg/mL ox-LDL处理分化后的细胞24h。用预冷PBS洗2次,60%异丙醇固定5min,0.3%油红O染色液染色15min,洗去染色液,倒置显微镜下观察,巨噬泡沫细胞内有大量红色脂肪滴的存在,表明THP-1巨噬细胞已经泡沫化。
2)药物处理方法
随机分为6组,分别为正常组、高剂量对照组、模型组、高剂量治疗组、中剂量治疗组、低剂量治疗组。其中模型组为80μg/mL的ox-LDL处理THP-1巨噬细胞24h, SPae治疗组中SPae预孵育2h后,加入80μg/mL的ox-LDL共孵育24h,高、中、低剂量分别是40μM、20μM、10μM SPae。
3)油红O染色
按照方法2处理好的细胞,用60%异丙醇固定5min,0.3%油红O染色液染色15min,PBS洗2遍,水性封片剂封片。荧光显微镜下白光观察,随机拍照。
4)细胞内胆固醇含量的测定及ROS、NO、SOD检测
按照方法2处理好的细胞,根据细胞内胆固醇测定试剂盒说明书,检测细胞内总胆固醇、胆固醇酯的含量；及按照ROS、NO、SOD各试剂盒操作测定活性氧族、一氧化氮、超氧化物歧化酶。
5)SPae对THP-1巨噬细胞与Dil-oxLDL结合的影响
4-C下10μg/mL Dil-oxLDL与按照方法2处理好的细胞孵育2h,PBS洗3次,用激光共聚焦显微镜(400×)随机拍照,激发波波长520nm和发射波波长580nm。
6)SPae对THP-1巨噬细胞与Dil-oxLDL摄取的影响
4-C下10μg/mL Dil-oxLDL与按照方法2处理好的细胞孵育4h,PBS洗3次,用激光共聚焦显微镜(400×)随机拍照,激发波波长520nm和发射波波长580nm。
7)SPae对THP-1巨噬细胞清道夫受体CD36与SR-A表达的影响
按照方法2处理好的细胞,Western Blot分析SPae对THP-1巨噬细胞清道夫受体CD36与SR-A表达的影响。
8)SPae对THP-1巨噬细胞ATP结合盒转运蛋白A1(ABCA1)的表达的影响
按照方法2处理好的细胞,Western Blot分析SPae对THP-1巨噬细胞ABCA1表达的影响。
9)检测过氧化物酶体增殖物激活受体γ(PPARγ)、 NF-κB、P38、JNK以及氧化应激的影响。
Western Blot检测ox-LDL对THP-1巨噬细胞的NF-κB抑制因子α(IκBα)、IκB激酶β (IKKβ)、P38、pP38、PPARγ、JNK和P-JNK蛋白表达的影响。按照NO、SOD、LDH试剂盒操作测定一氧化氮、超氧化物歧化酶、活性氧。
10)apoE-/-小鼠动脉硬化模型的建立
选用15只雄性apoE基因敲除小鼠,3只野生型雄性C57BL/6J小鼠组,其中apoE基因敲除小鼠随机分成5组,分别是模型组、高剂量对照组、高剂量防治组、中剂量防治组、低剂量防治组,每组3只。实验开始时,所有动物同步给药,每天给药一次,并同时高脂喂食,连续给药喂食12周。
11)免疫组化与免疫荧光
麻醉小鼠,取出解剖分离心脏,主动脉,蔗糖梯度溶液中脱水,OCT包埋组织,冰冻切片机切片,主动脉按冠状切面切取厚度为81μm的组织切片,-80℃保存。油红O染色,倒置显微镜下观察主动脉窦部和主动脉红色的动脉粥样硬化斑块的情况；免疫组化的方法检测斑块内1mac-3、VCAM-1的水平；应用免疫荧光的方法,检测PECAM-1,评价主动脉根部血管内皮完整性。
12)血清ICAM-1、VCAM-1、TNF-α、MCP-1、IL-8和LDL-C水平水平
小鼠麻醉后,自小鼠摘除眼球,分离血清,并分别检测血清ICAM-1、 VCAM-1、TNF-α、MCP-1和IL-8水平和低密度脂蛋白胆固醇(LDL-C)含量。
结果：
1)巨噬细胞泡沫化模型建立成功；
2)SPae浓度依赖性抑制THP-1巨噬细胞泡沫化的形成；
3)SPae一方面抑制THP-1巨噬细胞SRA和CD36的表达,降低THP-1巨噬细胞与Dil-ox-LDL的结合和摄取能力,另一方面提高ABCA1的表达,加强胞内游离胆固醇逆转运出细胞；
4)小鼠在体模型显示,SPae抑制动脉硬化斑块蓄积,同时减轻在体炎症反应。
结论：
SPse可调控PPARγ和NF-κB活性和氧化应激反应,调控清道夫受体和ATP结合盒转运蛋白A1的表达,并调节动脉粥样硬化过程中炎症的产生,达到抗动脉粥样硬化的目的。
背景
与非糖尿病患者相比,糖尿病能显著增加心血管疾病的发病率和死亡率。迄今为止,冠脉支架已广泛地应用于临床急性冠心病事件；它可以明显地改善患者的临床预后,且具有较高的操作成功率和良好的早期临床效果。虽然传统的金属裸支架已深入应用于各种冠心病患者,并取得了一定的疗效；然而,其长期预后和再狭窄率一直困扰着临床医师。近些年来,西罗莫司洗脱支架被用来治疗裸金属支架术后再狭窄和初次冠脉狭窄,并取得长足的进步。一直来,国内外对冠心病合并糖尿病-------这群特殊患者的治疗探索从未停顿；但其在不同的临床试验中,西罗莫司洗脱支架和裸金属支架治疗该类患者的疗效和安全性,仍具相当的争议性。
目的
通过Meta分析方法,在较大样本量的前提下,评价西罗莫司洗脱支架与金属裸支架治疗冠心病合并糖尿病的西方人群和中国人群的临床疗效和安全性。
方法
制定了详细的纳入与排除标准后,同时根据拟定的上述标准制定出全面、系统的检索策略；要求所选择的文献设计类型为国内外的临床对照实验。中文检索关键词：雷帕霉素洗脱支架；西罗莫司洗脱支架；金属裸支架；糖尿病；冠心病。英文检索关键词：rapamycin eluting stent; sirolimus eluting stent; bare metal stents; diabetes; coronary arterial disease。按照改良Jadad评分标准,两位独立的研究人员对纳入研究的每篇文献做质量评价,遇到争议之处,通过协商解决；无法达成一致时,向第三位评价者询问,1-3分为低质量,4-7分为高质量。纳入文献的结果测量指标为二分类变量,采用优势比(Odds Ratio, OR)作为疗效分析的统计量,使用95%可信区间(confidence interval, CI)表示。统计结果以森林图表示。分别用漏斗图、Begger's和Egger's检验三种方法评估发表偏倚。
结果
最终纳入18篇符合标准的文献。包括西罗莫司洗脱支架组的1764例和金属裸支架组的1912例病例。西方人群的10篇文献得分在2-7之间,其中2篇低质量文献,8篇属于高质量文献；而中国人群的8篇文献得分在1-2之间,均属于低质量文献。在西方人群的研究,SEM组的靶病变血运重建率均显著的低于BMS组,合并效应量为0.26,95%可信区间为(0.16,0.45)；在中国人群的研究,SEM组的靶病变血运重建率均显著的低于BMS组,合并效应量为0.30,95%可信区间为(0.14,0.62)。在西方人群的研究,SEM组的心肌梗死发生率低于BMS组,合并效应量为0.94,95%可信区间为(0.66,1.35)；在中国人群的研究,SEM组的心肌梗死发生率低于BMS组,合并效应量为0.64,95%可信区间为(0.31,1.31)。西方人群的研究SEM组的平均死亡率高于BMS组,合并效应量为1.11,95%可信区间为(0.72,1.73),而中国人群的研究SEM组的平均死亡率低于BMS组,合并效应量为0.62,95%可信区间为(0.22,1.76)。西方人群的研究,SEM组的主要心血管不良事件发生率显著的低于BMS组,合并效应量为0.40,95%可信区间为(0.28,0.58)；中国人群的研究,SEM组的主要心血管不良事件发生率显著的低于BMS组,合并效应量为0.25,95%可信区间为(0.15,0.42)。西方人群的亚组分析显示SEM组的主要心血管不良事件发生率显著的低于BMS组,当样本量≤90,合并效应量为0.30,95%可信区间为(0.19～0.47)；随机对照试验的亚组分析,合并效应量为0.30,95%可信区间为(0.22～0.40)；欧洲人群的亚组分析,合并效应量为0.42,95%可信区间为(0.32～0.56)。
结论
1、在西方人群与中国人群的研究,SEM组的靶病变血运重建率均显著的低于BMS组。
2、在西方人群与中国人群的研究,SEM组的心肌梗死发生率均低于BMS组,但差异均无统计学意义。
3、西方人群的研究SEM组的平均死亡率高于BMS组,而中国人群的研究SEM组的平均死亡率低于BMS组,但差异均无统计学意义。
4、在西方人群与中国人群的研究,SEM组的主要心血管不良事件发生率均显著的低于BMS组。
SEM较BMS更加适合治疗伴有糖尿病的冠心病患者。
Background
Chronic inflammation plays a crucial role in the initiation and progression of atherosclerosis (AS) and endothelial disorder plays a major role in the early stage of AS. Under the effects of multiple pathogenic factors, vascular endothelial cells are activated and the expressions of adhesion molecules, pro-inflammatory cytokines and chemokine receptor are increased, which assist the infiltration of inflammatory cells and results in endothelial dysfunction, increase of oxidative stress, apoptosis, lipidosis and finally occurrence of AS.
The activation of transcription factor NF-κB is closely correlated with the occurrence and development of inflammatory response of AS. NF-κB is homogenous or heterogeneous dimmer composed of P50, P52, P65, RelB and c-Rel, and is involved in the modulation of pathophysiology processes such as immune, inflammation and proliferation. Under the normal condition of cells, the components of NF-κB are constrained in the cytoplasm. Under the exogenous stimulation, IκBs can be activated by the upstream IκB kinase (IKK) complex, phosphorylated, ubiquitinated and degraded by protease, which finally results in the release of NF-κB (predominantly in dimmer of P65/P50) and translocation from cytoplasm to nuclei to modulate the transcription and expression of target genes.
Oxidative stress plays important role in formation process of AS. Oxidative stress is the imbalance between the generation of excessive active oxygen and the anti-oxygenation system clearing active oxygen. Active oxygen can affect many functions of vascular endothelia, such as the phenotype modulation of growth, apoptosis and survival of vascular endothelial cells and smooth muscle cells, the endothelia-dependent vascular dilation, the damage of vascular wall due to lacking NO bioactivity, the adhesion increase of monocytes and the angiogenesis.
As a new kind of compound of paeonol extracted from the moutan bark and after sulfonation and salifying, sodium paeonol sulfonate has multiple effects in anti-inflammation, pain-killing, antitumor, anti-lipid peroxidation, and immunity modulation. Recent study indicated that sodium paeonol sulfonate has effect in anti-AS, but the mechanism of which is not clear. Therefore, the present study investigated the effect of sodium paeonol sulfonate on the vascular inflammation and its possible mechanism.
Objectives
1. To investigate the effect of sodium paeonol sulfonate on the expressions of adhesion molecules, pro-inflammatory cytokines and chemokine receptor in monocytes induced by TNF-a.
2. To investigate the effects and possible mechanism of sodium paeonol sulfonate on the NF-κB activation and oxidative stress in endothelial cells induced by TNF-a.
Methods
1) Culture of human aortic endothelial cells
Human aortic endothelial cells (HAECs) were cultured with ECM medium containing20%FBS in5%CO2incubator at37℃and changed with medium every3days. Passaging and plating were completed as required.
2) Establishment of cell model
HAECs were incubated with5,10and20ng/ml TNF-a, respectively, for24h. The expressions of ICAM-1and VCAM-1were examined with Western Blot.
3) Adhesion experiment of monocytes
THP-1cells labeled with calcein-AM at final concentration of5μmol/L were co-cultured with HAECs in dark at37℃for2h. The cells were rinsed with PBS for2-3times to remove un-adhered cells and added2ml PBS to be observed under confocal microscopy. The excitation wavelength and emission wavelength was485nm and530nm, respectively.
4) ROS measurement
According to the manual of ROS kit, DCFH-DA was used to measure the release of intracellular superoxides after treatment with sodium paeonol sulfonate.
5) NO,SOD and LDH measurements
NO,SOD and LDH were measured according to the manuals of kits respectively.
6) Protein measurement with Western blot
The expressions of ICAM-1and VCAM-1, the phosphorylation of p-eNOS, and the activities of NF-κB and p-IKKβ were measured with Western blot.
7) Establishment of in vivo inflammation of mice
The in vivo inflammation of mice was established by intraperitoneal injection of30μg/kg TNF-a.
8) Measurement of serum ICAM-1, VCAM-1, IL-8and MCP-1
The levels of serum ICAM-1, VCAM-1, IL-8and MCP-1were measured with artery blood according to the manual of ELISAkit.
9) Immunohistochemistry
Under deep anesthesia, the thoracic aorta was removed, dehydrated in gradient sucrose solution, embedded with paraffin, cut for coronary slices with a Fully Motorized Rotary Microtome at4μm and stored at-80℃. The tissue staining was performed according to the procedure of ICAM-1and VCAM-1staining kit.
Results
1. Sodium paeonol sulfonate can inhibit the expressions of ICAM-1and VCAM-1, reduce the release of ROS, increase the production of NO and SOD, decrease the vascular inflammatory response, respectively induced by TNF-α.
2. Sodium paeonol sulfonate increased the phosphorylation of endothelial eNOS and decreased the activities of NF-κB and the expressions of p-IKKβ, respectively induced by TNF-α.
3. Sodium paeonol sulfonate inhibited the vascular inflammation induced by TNF-a in in vivo model.
Conclusion
Sodium paeonol sulfonate can inhibit the expressions of ICAM-1and VCAM-1, reduce the release of ROS, increase the production of NO and SOD, decrease the vascular inflammatory response, induced by TNF-α, and maintain the normal function of endothelial cells.
Background
Foamy macrophages and inflammatory factors play important roles in atherosclerosis (AS). Endothelial dysfunction is the initial factor of AS while metabolism disorder of lipid is the key step of AS. Oxidative stress can induce endothelial injury and modify LDL to ox-LDL which can aggravate endothelial inflammation and promote macrophages to form foamy cells. After apoptosis or necrosis, the lipid in foamy cells is released to form stripped atherosclerotic plaque. Therefore, the formation of foamy cells plays same important role in the occurrence and development of AS.
The extracted paeonol from moutan bark is formed of sodium paeonol sulfonate (Spae) through sulfonation and salifying, and has many effects including anti-inflammation, pain killing, anti-tumor, anti-lipid oxygenation, immune modulation. From previous chapter, we have found that Spae has effects in antagonizing the oxidative stress and vascular inflammation induced by TNF-a. Simultaneously, many studies have confirmed that the formation of foamy cells accompanies the formation of inflammation and the continuity of oxidative stress. In the present section, we further investigated the inhibitory effect of SPae on the foamy macrophages and AS induced by ox-LDL.
Therefore, the present study investigated the effect of SPae on the foamy macrophages and AS formation induced by ox-LDL from the three features in cell model and in vivo model:(1) establishing the model of foamy macrophages to observe the effects of SPae on the phagocytosis of ox-LDL by foamy macrophages and on the expressions of scavenge receptor A (SRA), CD36and ATP-binding cassette transport protein A1(ABCA1);(2) using apoE-/-mouse AS model to study the therapeutic effect of SPae on AS;(3) to investigate its potential mechanism at molecular level.
Objectives
1) To investigate the effect of SPae on the formation of foamy macrophages.
2) To investigate the effect of SPae on the early plaque of AS in vector model.
Methods
1) Establishment and identification of foamy macrophages
THP-1cells were induced to differentiate for24h by100ng/ml PMA. The differentiated cells were treated with80μg/mL ox-LDL for24h, rinsed with pre-cooled PBS twice, fixed with60%isopropanol for5min, stained with0.3%rathonum red solution for15min. After removal of staining solution, the cells were observed under inverted microscopy. Existence of massive red lipid drops in foamy macrophages demonstrated formation of foamy macrophages from THP-1cells.
2) Treatment of cells
The cells were randomly divided into6groups:normal group, high-dosage control group, model group, high-dosage group, middle-dosage group and low-dosage group. For model group, THP-1macrophages were treated with80μg/mL ox-LDL for24h. For SPae treatment groups, the cells were pre-incubated with SPae for2h, followed by co-incubation with SPae and80μg/mL ox-LDL for24h. The high, middle and low dosage of SPae was40μM,20μM and10μM, respectively.
3) Rathonum red staining
The cells treated as method2) were fixed with60%isopropanol for5min, stained with0.3%rathonum red solution for15min and rinsed with PBS twice. After mounting with aqueous mounting medium, the cells were observed under fluorescent microscopy and taken photos randomly.
4) Measurements of intracellular cholesterol, NO,SOD and ROS
The cells treated as method2) were measured of intracellular total cholesterol and cholesterol ester according to the kit manual. NO,SOD and ROS were measured according to the manuals of kits respectively.
5) Effect of SPae on the binding of THP-1macrophages with Dil-oxLDL
Under4℃, the cells treated as method2) were incubated with10μg/mL Dil-oxLDL for2h, rinsed3times and taken photos randomly with confocal microscopy (400x) with the excitation wavelength and emission wavelength of520nm and580nm, respectively.
6) Effect of SPae on the uptake of Dil-oxLDL in THP-1macrophages
Under4℃, the cells treated as method2) were incubated with10μg/mL Dil-oxLDL for4h, rinsed3times and taken photos randomly with confocal microscopy (400x) with the excitation wavelength and emission wavelength of520nm and580nm, respectively.
7) Effect of SPae on the expressions of CD36and SRA in THP-1macrophages
The cells treated as method2) were analyzed the effect of SPae on the expressions of CD36and SRA in THP-1macrophages, using Western blot.
8) Effect of SPae on the expression of ABCA1in THP-1macrophages
The cells treated as method2) were analyzed the effect of SPae on the expression of ABCA1in THP-1macrophages, using Western blot.
9) Measurement of effects of ox-LDL on PPARγ, NF-κB, pP38, JNK and oxidative stress.
Western Blot was used to measure the effects of ox-LDL on the expressions of IKKβ, β-IKKβ, p-IKBα, IkBα, P38, pP38, PPARγ, JNK and P-JNK in THP-1macrophages. NO,SOD and ROS were measured according to the manuals of kits respectively.
10) Establishment of apoE-/-mouse AS model
Fifteen male apoE knockout (apoE-/-) mice and3wild-type male C57BL/6J mice were used. apoE-/-mice were randomly divided into model group, high-dosage group, middle-dosage group and low-dosage group,3mice for each group. From the beginning, all animal were synchronously administrated with chemical once every day and high-fat food, for consecutively16weeks
11) Immunohistochemistry and immunofluorescence
Under deep anesthesia, the hear and thoracic aorta were removed, dehydrated in gradient sucrose solution, embedded with OCT, cut for coronary slices with cryomicrotome at8um and stored at-80℃. The tissues were stained with rathonum red and observed under inverted microscopy for the red AS plaque in the aortic sinus and aorta. Immunohistochemical method was used to measure the levels of mac-3and VCAM-1in plaque. Immunofluorescent method was used to measure the PEC AM-1to evaluate the integrity of vascular endothelia of aortic root.
12) Serum levels of ICAM-1, VCAM-1, TNF-a, MCP-1, IL-8and LDL-C
After anesthesia, the eyes of mice were taken out to separate serum. The serum levels of ICAM-1, VCAM-1, TNF-α, MCP-1, IL-8and LDL-C were measured.
Results
1) Successful establishment of foamy macrophages;
2) SPae dose-dependently inhibited THP-1to form foamy macrophages;
3) SPae inhibited the expressions of SRA and CD36in THP-1macrophages, decreased the binding of Dil-ox-LDL to and the uptake of Dil-ox-LDL by THP-1macrophages, increased the expression of ABCA1, and enhanced the transportation of intracellular free cholesterol to extracellular space;
4) SPae inhibited the accumulation of AS plaque and reduced the inflammatory response in in vivo mice model.
Conclusion
Through modulating the activities of PPARy and NF-κB and the oxidative stress, and modulating the expressions of SRA and ABCA1and the formation of inflammation during AS, SPae achieves the anti-AS effect.
Background
Compared with patients without diabetes, patients with diabetes mellitus (DM) had significantly increased cardiovascular morbidity and mortality. So far,coronary stent had been widely used for revascularization in acute cardiac events and proved to improved prognosis, with a high success rate and favorable early outcome. The traditional bare-metal stent (BMS) had been initially widely used for treatment of coronary heart disease and had considerable efficacy and safety. However, the long term outcome and restenosis rate has been very discouraging. Recently, sirolimus-eluting stents (SES) had been increasingly performed for treating restenosis after BMS as well as the native coronary narrowing, and made therapeutic progress. Efforts to explore the treatment of coronary heart disease patients with diabetes mellitus at home and abroad has never been interrupted.For coronary arterial disease (CAD) patients with diabetes, the outcome, the efficacy and safety of SES and BMS remain controversial in different clinical trials.
Objective
To compare the efficacy and safety of sirolimus eluting and bare metal stents in CAD patients with diabetes by meta-analysis.
Methods:
The clinical trials were searched according to the detailed inclusion and exclusion criteria, The following key words were used in Chinese,"rapamycin eluting stent;,sirolimus eluting stent, bare metal stent, diabetes, coronary heart disease". The following key words were used in English,"rapamycin eluting stent,sirolimus eluting stent, bare metal stent, diabetes, coronary arterial disease". According to modified Jadad score, two independent researchers included in the study evaluated the quality of each article separately. When consensus can not be reached at the controversial point, the third reviewer were asked and resolved the discrepancies. Grade1-3belongs to low quality and4-7to high quality. If the results of the measurement indexes from the included literatures being dichotomous variables, Odds ratio (OR) and95%confidence intervals (CI) were estimated in each study. Statistical results were expressed in the forest plots and publication bias was evaluated with funnel plots, Begger's and Egger's test.
Results:
Meta-analysis was then performed in a total of1764patients of SEM group and1912patients of BMS group with diabetes from18studies. Authenticity was evaluated for all literatures included in the study according to modified Jadad quality assessment form.10literatures of Western populations were scored between2-7, including two low-quality documents and eight the high-quality literatures,while the8literatures of Chinese populations scored between1-2,belonged to the low-quality literatures. In the research of Western populations, compared with those in bare-metal stent group, the subjects in sirolimus-eluting stent group had reduced risk for target lesion revascularization (OR0.26,95%confidence interval (CI)0.16-0.45), and for major adverse cardiac events (OR0.40,95%CI0.28-0.58). There was no difference for myocardial infarction event (OR0.94,95%CI0.66-1.35)or mortality event (OR1.11,95%CI0.72-1.73). In the research of Chinese populations, compared with those in bare-metal stent group, the subjects in sirolimus-eluting stent group had reduced risk for target lesion revascularization (OR0.30,95%CI0.14,0.62), and for major adverse cardiac events (OR0.25,95%CI0.15-0.42). There was no difference for myocardial infarction event (OR0.64,95%CI0.31-1.31) or mortality event (OR0.62,95%CI0.22-1.76). Subgroup analysis showed significant difference for overall risk of major cardiac events between SES and BMS, when the sample size was<90(OR0.30,95%CI0.19～0.47), when it was randomized control trial (RCT)(OR0.30,95%CI0.22～0.40), or when it was performed in Europeans (OR0.42,95%CI0.32～0.52).
Conclusion:
1、In the research of Chinese and Western populations, target lesion revascularization rate in SEM group was significantly less than that of BMS group.
2、In the research of Chinese and Western populations, incidence of myocardial infarction in SEM group was less than that of BMS group, but the difference was not statistically significant.
3、In the research of Western populations, mortality event in SEM group were more than the BMS group, and in the research of Chinese populations, mortality event rate in SEM group were less than that of BMS group., but the difference was not statistically significant.
4、In the research of Chinese and Western populations, incidence of major cardiac events in SEM group was significantly less than that of BMS group.
Our study confirmed that SES is more effective and safer than BMS in CAD patients with diabetes.
血管的慢性炎症贯穿整个动脉粥样硬化(atherosclerosis, AS)的发生发展过程。特别是在动脉粥样硬化早期阶段,内皮功能障碍发挥了主要的作用。在多种致病因素的作用下,血管内皮细胞活化,粘附分子、致炎细胞因子及化学趋化因子的表达增加,协助炎症细胞浸润,造成内皮功能障碍、氧化应激增加,细胞凋亡、脂质沉积,最终导致动脉硬化的发生。
转录因子κB (NF-κB)活化与动脉粥样硬化的炎症反应发生和发展密切相关。NF-κB是由P50, P52, P65, Re1B和c-Rel等五种分子组成的同源或异源二聚体并参与调控体内病理生理如免疫、炎症、增殖等过程。在细胞处于正常状态时,NF-κB的组成成分限制在胞浆中,而当细胞受到外界刺激后,NF-κB抑制因子(IκBs)被其上游的IκB激酶(IKK)复合物激活,发生磷酸化,随后被泛素化及蛋白酶体降解,最终导致NF-κB(主要是P65/P50二聚体形式)的释放并由胞浆转位至胞核,参与调控目的基因的转录及表达。
在动脉粥样硬化形成的过程中,氧化应激发挥着重大作用。氧化应激是过量的活性氧与内源性清除活性氧的抗氧化系统间失去平衡。活性氧影响血管内皮的很多功能,如介导血管内皮细胞和平滑肌细胞生长、凋亡和存活等表型调节,内皮依赖的血管扩张,参与血管壁缺失一氧化氮(NO)生物活性而损伤,增加单核细胞粘附和在血管生成中起作用。
丹皮酚磺酸钠(Sodium Paeonolsilate, SPae)是从中药牡丹皮中分离提取的丹皮酚经磺化、成盐形成的一种新的化合物,具有抗炎、止痛、抗肿瘤、抗脂质过氧化、免疫调节等多重作用,近年有研究表明其具有抗动脉粥样硬化作用,但具体作用机制仍不清楚。因此,我们观察了丹皮酚磺酸钠对血管炎症影响,并探讨其可能的作用机制。
目的
1.研究丹皮酚磺酸钠对肿瘤坏死因子α (TNF-a)诱导的单核细胞粘附分子、致炎因子及化学趋化因子受体表达的影响。
2.研究丹皮酚磺酸钠对TNF-α诱导内皮细胞的NF-κB活性、氧化应激的影响及可能的机制。
方法
1)人动脉内皮细胞1human aortic endothelial cells, HAECs)的培养
人动脉内皮细胞(himan aortic endothelial cells, HAECs)培养在含有10%FBS的ECM培养基中,置于5%C02,37℃培养箱中培养,每三天换一次液,并根据需要进行传代和铺板。
2)细胞模型的建立
HAECs与5,10和20ng/ml的fNF-α共孵育24h, Western Blot检测内皮细胞ICAM-1和VCAM-1的表达。
3)单核细胞粘附实验
用终浓度为5μmol/L的钙黄绿素-AM (calcein-AM)标记的THP-1细胞接种在HAECs上。避光条件下,37℃共同孵育2h。用PBS轻轻清洗细胞2-3次,去除未粘附的单核细胞,加入2mlPBS,于激光共聚焦显微镜下观察,激发波长485nm,发射波长530nm。
4) ROS检测
按照ROS试剂盒操作说明,运用二氯二氢荧光素-乙酰乙酸酯(DCFH-DA)探针检测丹皮酚磺酸钠处理后,细胞内超氧化物的释放情况。
5) NO、超氧化物歧化酶(SOD)、乳酸脱氢酶(LDH)检测
按照NO、SOD、LDH试剂盒操作测定一氧化氮、超氧化物歧化酶、乳酸脱氢酶。
6) Western blot蛋白检测
检测丹皮酚磺酸钠处理后,细胞间粘附分子-1(ICAM-1)、血管细胞粘附分子-1(VCAM-1)的表达,磷酸化内皮型一氧化氮合酶(p-eNOS),以及NF-κB.p-IKKβ活性。
7)小鼠在体炎症模型的建立
本实验采用30μg/kg TNF-α经腹腔注射(i.p.)48h建立小鼠在体炎症模型。
8)血清中ICAM-1、VCAM-1、白介素8(IL-8)、单核细胞趋化蛋白1(MCP-1)检测
取动脉血,按照ELISA试剂盒说明,检测血浆中ICAM-1、VCAM-1、IL-8、MCP-1水平。
免疫组化
麻醉小鼠,取出胸主动脉,蔗糖梯度溶液中脱水,石蜡包埋组织,石蜡切片机切片,主动脉按冠状切面切取厚度为4μm的组织切片,-80℃保存。按照操作步骤进行ICAM-1和VCAM-1的组织染色。
结果
1.丹皮酚磺酸钠能够抑制TNF-α诱导的ICAM-1和VCAM-1的表达,减少活性氧簇(ROS)释放,增加NO、SOD的生成。
2.丹皮酚磺酸钠上调TNF-α诱导的内皮细胞eNOS磷酸化水平和降低NF-κB活性及p-IKKβ的表达。
3.丹皮酚磺酸钠在体模型上抑制TNF-α诱导的血管炎症反应。
结论
丹皮酚磺酸钠能够抑制TNF-α诱导的ICAM-1和VCAM-1的表达,减少活性氧簇(ROS)释放,增加NO、SOD的生成,降低血管炎症反应,维持内皮细胞正常功能。
背景
巨噬细胞泡沫化和炎症因子在动脉粥样硬化(AS)发生发展中扮演了重要角色。内皮功能障碍被是AS的始动因素,而脂质代谢紊乱是AS发生的关键环节。氧化应激一方面引起内皮损伤,另一方面修饰LDL成氧化低密度脂蛋白(ox-LDL)。 ox-LDL-一方面加剧内皮炎症,另一方面加速巨噬细胞形成泡沫细胞。而泡沫细胞凋亡或坏死后,将细胞内的脂质释放出来,形成条纹状粥样硬化斑块。由此可见,泡沫细胞的形成在动脉粥样硬化的发生、发展中同样扮演着一个十分重要的角色。
从中药牡丹皮中分离提取的丹皮酚经磺化、成盐形成的丹皮酚磺酸化钠(Spae),具有抗炎、止痛、抗肿瘤、抗脂质过氧化、免疫调节等多重作用,我们上一章节已经发现SPae具有抵抗肿瘤坏死因子α(TNF-a)诱导的氧化应激效应和抗血管炎症。同时,众多研究证明细胞泡沫化形成也伴随着炎症的产生和氧化应激的的继续,我们进一步观察SPae是否抑制ox-LDL诱导的巨噬细胞泡沫化和动脉粥样硬化形成。
为此,本课题从以下三个方面在细胞模型和在体模型探讨SPae对ox-LDL诱导的巨噬细胞泡沫化和动脉粥样硬化形成的影响。1.建立巨噬细胞泡沫化细胞模型,并观察SPae对巨噬细胞泡沫化吞噬ox-LDL能力的影响,以及对清道夫受体CD36、清道夫受体A (SRA)和ATP结合盒转运蛋白A1(ABCA1)的表达的影响；2.采用apoE-/-小鼠动脉硬化模型,研究SPae对AS的治疗作用；3.从分子水平探讨其潜在的作用机制。
目的：
1)研究APse对巨噬细胞泡沫化形成的影响
2)探讨载体模型中,SPae对AS早期斑块发展的影响。
方法：
1)巨噬细胞泡沫化模型建立与鉴定
THP-1细胞经10Ong/ml丙二醇甲醚醋酸酯(PMA)诱导分化24h后,80μg/mL ox-LDL处理分化后的细胞24h。用预冷PBS洗2次,60%异丙醇固定5min,0.3%油红O染色液染色15min,洗去染色液,倒置显微镜下观察,巨噬泡沫细胞内有大量红色脂肪滴的存在,表明THP-1巨噬细胞已经泡沫化。
2)药物处理方法
随机分为6组,分别为正常组、高剂量对照组、模型组、高剂量治疗组、中剂量治疗组、低剂量治疗组。其中模型组为80μg/mL的ox-LDL处理THP-1巨噬细胞24h, SPae治疗组中SPae预孵育2h后,加入80μg/mL的ox-LDL共孵育24h,高、中、低剂量分别是40μM、20μM、10μM SPae。
3)油红O染色
按照方法2处理好的细胞,用60%异丙醇固定5min,0.3%油红O染色液染色15min,PBS洗2遍,水性封片剂封片。荧光显微镜下白光观察,随机拍照。
4)细胞内胆固醇含量的测定及ROS、NO、SOD检测
按照方法2处理好的细胞,根据细胞内胆固醇测定试剂盒说明书,检测细胞内总胆固醇、胆固醇酯的含量；及按照ROS、NO、SOD各试剂盒操作测定活性氧族、一氧化氮、超氧化物歧化酶。
5)SPae对THP-1巨噬细胞与Dil-oxLDL结合的影响
4-C下10μg/mL Dil-oxLDL与按照方法2处理好的细胞孵育2h,PBS洗3次,用激光共聚焦显微镜(400×)随机拍照,激发波波长520nm和发射波波长580nm。
6)SPae对THP-1巨噬细胞与Dil-oxLDL摄取的影响
4-C下10μg/mL Dil-oxLDL与按照方法2处理好的细胞孵育4h,PBS洗3次,用激光共聚焦显微镜(400×)随机拍照,激发波波长520nm和发射波波长580nm。
7)SPae对THP-1巨噬细胞清道夫受体CD36与SR-A表达的影响
按照方法2处理好的细胞,Western Blot分析SPae对THP-1巨噬细胞清道夫受体CD36与SR-A表达的影响。
8)SPae对THP-1巨噬细胞ATP结合盒转运蛋白A1(ABCA1)的表达的影响
按照方法2处理好的细胞,Western Blot分析SPae对THP-1巨噬细胞ABCA1表达的影响。
9)检测过氧化物酶体增殖物激活受体γ(PPARγ)、 NF-κB、P38、JNK以及氧化应激的影响。
Western Blot检测ox-LDL对THP-1巨噬细胞的NF-κB抑制因子α(IκBα)、IκB激酶β (IKKβ)、P38、pP38、PPARγ、JNK和P-JNK蛋白表达的影响。按照NO、SOD、LDH试剂盒操作测定一氧化氮、超氧化物歧化酶、活性氧。
10)apoE-/-小鼠动脉硬化模型的建立
选用15只雄性apoE基因敲除小鼠,3只野生型雄性C57BL/6J小鼠组,其中apoE基因敲除小鼠随机分成5组,分别是模型组、高剂量对照组、高剂量防治组、中剂量防治组、低剂量防治组,每组3只。实验开始时,所有动物同步给药,每天给药一次,并同时高脂喂食,连续给药喂食12周。
11)免疫组化与免疫荧光
麻醉小鼠,取出解剖分离心脏,主动脉,蔗糖梯度溶液中脱水,OCT包埋组织,冰冻切片机切片,主动脉按冠状切面切取厚度为81μm的组织切片,-80℃保存。油红O染色,倒置显微镜下观察主动脉窦部和主动脉红色的动脉粥样硬化斑块的情况；免疫组化的方法检测斑块内1mac-3、VCAM-1的水平；应用免疫荧光的方法,检测PECAM-1,评价主动脉根部血管内皮完整性。
12)血清ICAM-1、VCAM-1、TNF-α、MCP-1、IL-8和LDL-C水平水平
小鼠麻醉后,自小鼠摘除眼球,分离血清,并分别检测血清ICAM-1、 VCAM-1、TNF-α、MCP-1和IL-8水平和低密度脂蛋白胆固醇(LDL-C)含量。
结果：
1)巨噬细胞泡沫化模型建立成功；
2)SPae浓度依赖性抑制THP-1巨噬细胞泡沫化的形成；
3)SPae一方面抑制THP-1巨噬细胞SRA和CD36的表达,降低THP-1巨噬细胞与Dil-ox-LDL的结合和摄取能力,另一方面提高ABCA1的表达,加强胞内游离胆固醇逆转运出细胞；
4)小鼠在体模型显示,SPae抑制动脉硬化斑块蓄积,同时减轻在体炎症反应。
结论：
SPse可调控PPARγ和NF-κB活性和氧化应激反应,调控清道夫受体和ATP结合盒转运蛋白A1的表达,并调节动脉粥样硬化过程中炎症的产生,达到抗动脉粥样硬化的目的。
背景
与非糖尿病患者相比,糖尿病能显著增加心血管疾病的发病率和死亡率。迄今为止,冠脉支架已广泛地应用于临床急性冠心病事件；它可以明显地改善患者的临床预后,且具有较高的操作成功率和良好的早期临床效果。虽然传统的金属裸支架已深入应用于各种冠心病患者,并取得了一定的疗效；然而,其长期预后和再狭窄率一直困扰着临床医师。近些年来,西罗莫司洗脱支架被用来治疗裸金属支架术后再狭窄和初次冠脉狭窄,并取得长足的进步。一直来,国内外对冠心病合并糖尿病-------这群特殊患者的治疗探索从未停顿；但其在不同的临床试验中,西罗莫司洗脱支架和裸金属支架治疗该类患者的疗效和安全性,仍具相当的争议性。
目的
通过Meta分析方法,在较大样本量的前提下,评价西罗莫司洗脱支架与金属裸支架治疗冠心病合并糖尿病的西方人群和中国人群的临床疗效和安全性。
方法
制定了详细的纳入与排除标准后,同时根据拟定的上述标准制定出全面、系统的检索策略；要求所选择的文献设计类型为国内外的临床对照实验。中文检索关键词：雷帕霉素洗脱支架；西罗莫司洗脱支架；金属裸支架；糖尿病；冠心病。英文检索关键词：rapamycin eluting stent; sirolimus eluting stent; bare metal stents; diabetes; coronary arterial disease。按照改良Jadad评分标准,两位独立的研究人员对纳入研究的每篇文献做质量评价,遇到争议之处,通过协商解决；无法达成一致时,向第三位评价者询问,1-3分为低质量,4-7分为高质量。纳入文献的结果测量指标为二分类变量,采用优势比(Odds Ratio, OR)作为疗效分析的统计量,使用95%可信区间(confidence interval, CI)表示。统计结果以森林图表示。分别用漏斗图、Begger's和Egger's检验三种方法评估发表偏倚。
结果
最终纳入18篇符合标准的文献。包括西罗莫司洗脱支架组的1764例和金属裸支架组的1912例病例。西方人群的10篇文献得分在2-7之间,其中2篇低质量文献,8篇属于高质量文献；而中国人群的8篇文献得分在1-2之间,均属于低质量文献。在西方人群的研究,SEM组的靶病变血运重建率均显著的低于BMS组,合并效应量为0.26,95%可信区间为(0.16,0.45)；在中国人群的研究,SEM组的靶病变血运重建率均显著的低于BMS组,合并效应量为0.30,95%可信区间为(0.14,0.62)。在西方人群的研究,SEM组的心肌梗死发生率低于BMS组,合并效应量为0.94,95%可信区间为(0.66,1.35)；在中国人群的研究,SEM组的心肌梗死发生率低于BMS组,合并效应量为0.64,95%可信区间为(0.31,1.31)。西方人群的研究SEM组的平均死亡率高于BMS组,合并效应量为1.11,95%可信区间为(0.72,1.73),而中国人群的研究SEM组的平均死亡率低于BMS组,合并效应量为0.62,95%可信区间为(0.22,1.76)。西方人群的研究,SEM组的主要心血管不良事件发生率显著的低于BMS组,合并效应量为0.40,95%可信区间为(0.28,0.58)；中国人群的研究,SEM组的主要心血管不良事件发生率显著的低于BMS组,合并效应量为0.25,95%可信区间为(0.15,0.42)。西方人群的亚组分析显示SEM组的主要心血管不良事件发生率显著的低于BMS组,当样本量≤90,合并效应量为0.30,95%可信区间为(0.19～0.47)；随机对照试验的亚组分析,合并效应量为0.30,95%可信区间为(0.22～0.40)；欧洲人群的亚组分析,合并效应量为0.42,95%可信区间为(0.32～0.56)。
结论
1、在西方人群与中国人群的研究,SEM组的靶病变血运重建率均显著的低于BMS组。
2、在西方人群与中国人群的研究,SEM组的心肌梗死发生率均低于BMS组,但差异均无统计学意义。
3、西方人群的研究SEM组的平均死亡率高于BMS组,而中国人群的研究SEM组的平均死亡率低于BMS组,但差异均无统计学意义。
4、在西方人群与中国人群的研究,SEM组的主要心血管不良事件发生率均显著的低于BMS组。
SEM较BMS更加适合治疗伴有糖尿病的冠心病患者。
Background
Chronic inflammation plays a crucial role in the initiation and progression of atherosclerosis (AS) and endothelial disorder plays a major role in the early stage of AS. Under the effects of multiple pathogenic factors, vascular endothelial cells are activated and the expressions of adhesion molecules, pro-inflammatory cytokines and chemokine receptor are increased, which assist the infiltration of inflammatory cells and results in endothelial dysfunction, increase of oxidative stress, apoptosis, lipidosis and finally occurrence of AS.
The activation of transcription factor NF-κB is closely correlated with the occurrence and development of inflammatory response of AS. NF-κB is homogenous or heterogeneous dimmer composed of P50, P52, P65, RelB and c-Rel, and is involved in the modulation of pathophysiology processes such as immune, inflammation and proliferation. Under the normal condition of cells, the components of NF-κB are constrained in the cytoplasm. Under the exogenous stimulation, IκBs can be activated by the upstream IκB kinase (IKK) complex, phosphorylated, ubiquitinated and degraded by protease, which finally results in the release of NF-κB (predominantly in dimmer of P65/P50) and translocation from cytoplasm to nuclei to modulate the transcription and expression of target genes.
Oxidative stress plays important role in formation process of AS. Oxidative stress is the imbalance between the generation of excessive active oxygen and the anti-oxygenation system clearing active oxygen. Active oxygen can affect many functions of vascular endothelia, such as the phenotype modulation of growth, apoptosis and survival of vascular endothelial cells and smooth muscle cells, the endothelia-dependent vascular dilation, the damage of vascular wall due to lacking NO bioactivity, the adhesion increase of monocytes and the angiogenesis.
As a new kind of compound of paeonol extracted from the moutan bark and after sulfonation and salifying, sodium paeonol sulfonate has multiple effects in anti-inflammation, pain-killing, antitumor, anti-lipid peroxidation, and immunity modulation. Recent study indicated that sodium paeonol sulfonate has effect in anti-AS, but the mechanism of which is not clear. Therefore, the present study investigated the effect of sodium paeonol sulfonate on the vascular inflammation and its possible mechanism.
Objectives
1. To investigate the effect of sodium paeonol sulfonate on the expressions of adhesion molecules, pro-inflammatory cytokines and chemokine receptor in monocytes induced by TNF-a.
2. To investigate the effects and possible mechanism of sodium paeonol sulfonate on the NF-κB activation and oxidative stress in endothelial cells induced by TNF-a.
Methods
1) Culture of human aortic endothelial cells
Human aortic endothelial cells (HAECs) were cultured with ECM medium containing20%FBS in5%CO2incubator at37℃and changed with medium every3days. Passaging and plating were completed as required.
2) Establishment of cell model
HAECs were incubated with5,10and20ng/ml TNF-a, respectively, for24h. The expressions of ICAM-1and VCAM-1were examined with Western Blot.
3) Adhesion experiment of monocytes
THP-1cells labeled with calcein-AM at final concentration of5μmol/L were co-cultured with HAECs in dark at37℃for2h. The cells were rinsed with PBS for2-3times to remove un-adhered cells and added2ml PBS to be observed under confocal microscopy. The excitation wavelength and emission wavelength was485nm and530nm, respectively.
4) ROS measurement
According to the manual of ROS kit, DCFH-DA was used to measure the release of intracellular superoxides after treatment with sodium paeonol sulfonate.
5) NO,SOD and LDH measurements
NO,SOD and LDH were measured according to the manuals of kits respectively.
6) Protein measurement with Western blot
The expressions of ICAM-1and VCAM-1, the phosphorylation of p-eNOS, and the activities of NF-κB and p-IKKβ were measured with Western blot.
7) Establishment of in vivo inflammation of mice
The in vivo inflammation of mice was established by intraperitoneal injection of30μg/kg TNF-a.
8) Measurement of serum ICAM-1, VCAM-1, IL-8and MCP-1
The levels of serum ICAM-1, VCAM-1, IL-8and MCP-1were measured with artery blood according to the manual of ELISAkit.
9) Immunohistochemistry
Under deep anesthesia, the thoracic aorta was removed, dehydrated in gradient sucrose solution, embedded with paraffin, cut for coronary slices with a Fully Motorized Rotary Microtome at4μm and stored at-80℃. The tissue staining was performed according to the procedure of ICAM-1and VCAM-1staining kit.
Results
1. Sodium paeonol sulfonate can inhibit the expressions of ICAM-1and VCAM-1, reduce the release of ROS, increase the production of NO and SOD, decrease the vascular inflammatory response, respectively induced by TNF-α.
2. Sodium paeonol sulfonate increased the phosphorylation of endothelial eNOS and decreased the activities of NF-κB and the expressions of p-IKKβ, respectively induced by TNF-α.
3. Sodium paeonol sulfonate inhibited the vascular inflammation induced by TNF-a in in vivo model.
Conclusion
Sodium paeonol sulfonate can inhibit the expressions of ICAM-1and VCAM-1, reduce the release of ROS, increase the production of NO and SOD, decrease the vascular inflammatory response, induced by TNF-α, and maintain the normal function of endothelial cells.
Background
Foamy macrophages and inflammatory factors play important roles in atherosclerosis (AS). Endothelial dysfunction is the initial factor of AS while metabolism disorder of lipid is the key step of AS. Oxidative stress can induce endothelial injury and modify LDL to ox-LDL which can aggravate endothelial inflammation and promote macrophages to form foamy cells. After apoptosis or necrosis, the lipid in foamy cells is released to form stripped atherosclerotic plaque. Therefore, the formation of foamy cells plays same important role in the occurrence and development of AS.
The extracted paeonol from moutan bark is formed of sodium paeonol sulfonate (Spae) through sulfonation and salifying, and has many effects including anti-inflammation, pain killing, anti-tumor, anti-lipid oxygenation, immune modulation. From previous chapter, we have found that Spae has effects in antagonizing the oxidative stress and vascular inflammation induced by TNF-a. Simultaneously, many studies have confirmed that the formation of foamy cells accompanies the formation of inflammation and the continuity of oxidative stress. In the present section, we further investigated the inhibitory effect of SPae on the foamy macrophages and AS induced by ox-LDL.
Therefore, the present study investigated the effect of SPae on the foamy macrophages and AS formation induced by ox-LDL from the three features in cell model and in vivo model:(1) establishing the model of foamy macrophages to observe the effects of SPae on the phagocytosis of ox-LDL by foamy macrophages and on the expressions of scavenge receptor A (SRA), CD36and ATP-binding cassette transport protein A1(ABCA1);(2) using apoE-/-mouse AS model to study the therapeutic effect of SPae on AS;(3) to investigate its potential mechanism at molecular level.
Objectives
1) To investigate the effect of SPae on the formation of foamy macrophages.
2) To investigate the effect of SPae on the early plaque of AS in vector model.
Methods
1) Establishment and identification of foamy macrophages
THP-1cells were induced to differentiate for24h by100ng/ml PMA. The differentiated cells were treated with80μg/mL ox-LDL for24h, rinsed with pre-cooled PBS twice, fixed with60%isopropanol for5min, stained with0.3%rathonum red solution for15min. After removal of staining solution, the cells were observed under inverted microscopy. Existence of massive red lipid drops in foamy macrophages demonstrated formation of foamy macrophages from THP-1cells.
2) Treatment of cells
The cells were randomly divided into6groups:normal group, high-dosage control group, model group, high-dosage group, middle-dosage group and low-dosage group. For model group, THP-1macrophages were treated with80μg/mL ox-LDL for24h. For SPae treatment groups, the cells were pre-incubated with SPae for2h, followed by co-incubation with SPae and80μg/mL ox-LDL for24h. The high, middle and low dosage of SPae was40μM,20μM and10μM, respectively.
3) Rathonum red staining
The cells treated as method2) were fixed with60%isopropanol for5min, stained with0.3%rathonum red solution for15min and rinsed with PBS twice. After mounting with aqueous mounting medium, the cells were observed under fluorescent microscopy and taken photos randomly.
4) Measurements of intracellular cholesterol, NO,SOD and ROS
The cells treated as method2) were measured of intracellular total cholesterol and cholesterol ester according to the kit manual. NO,SOD and ROS were measured according to the manuals of kits respectively.
5) Effect of SPae on the binding of THP-1macrophages with Dil-oxLDL
Under4℃, the cells treated as method2) were incubated with10μg/mL Dil-oxLDL for2h, rinsed3times and taken photos randomly with confocal microscopy (400x) with the excitation wavelength and emission wavelength of520nm and580nm, respectively.
6) Effect of SPae on the uptake of Dil-oxLDL in THP-1macrophages
Under4℃, the cells treated as method2) were incubated with10μg/mL Dil-oxLDL for4h, rinsed3times and taken photos randomly with confocal microscopy (400x) with the excitation wavelength and emission wavelength of520nm and580nm, respectively.
7) Effect of SPae on the expressions of CD36and SRA in THP-1macrophages
The cells treated as method2) were analyzed the effect of SPae on the expressions of CD36and SRA in THP-1macrophages, using Western blot.
8) Effect of SPae on the expression of ABCA1in THP-1macrophages
The cells treated as method2) were analyzed the effect of SPae on the expression of ABCA1in THP-1macrophages, using Western blot.
9) Measurement of effects of ox-LDL on PPARγ, NF-κB, pP38, JNK and oxidative stress.
Western Blot was used to measure the effects of ox-LDL on the expressions of IKKβ, β-IKKβ, p-IKBα, IkBα, P38, pP38, PPARγ, JNK and P-JNK in THP-1macrophages. NO,SOD and ROS were measured according to the manuals of kits respectively.
10) Establishment of apoE-/-mouse AS model
Fifteen male apoE knockout (apoE-/-) mice and3wild-type male C57BL/6J mice were used. apoE-/-mice were randomly divided into model group, high-dosage group, middle-dosage group and low-dosage group,3mice for each group. From the beginning, all animal were synchronously administrated with chemical once every day and high-fat food, for consecutively16weeks
11) Immunohistochemistry and immunofluorescence
Under deep anesthesia, the hear and thoracic aorta were removed, dehydrated in gradient sucrose solution, embedded with OCT, cut for coronary slices with cryomicrotome at8um and stored at-80℃. The tissues were stained with rathonum red and observed under inverted microscopy for the red AS plaque in the aortic sinus and aorta. Immunohistochemical method was used to measure the levels of mac-3and VCAM-1in plaque. Immunofluorescent method was used to measure the PEC AM-1to evaluate the integrity of vascular endothelia of aortic root.
12) Serum levels of ICAM-1, VCAM-1, TNF-a, MCP-1, IL-8and LDL-C
After anesthesia, the eyes of mice were taken out to separate serum. The serum levels of ICAM-1, VCAM-1, TNF-α, MCP-1, IL-8and LDL-C were measured.
Results
1) Successful establishment of foamy macrophages;
2) SPae dose-dependently inhibited THP-1to form foamy macrophages;
3) SPae inhibited the expressions of SRA and CD36in THP-1macrophages, decreased the binding of Dil-ox-LDL to and the uptake of Dil-ox-LDL by THP-1macrophages, increased the expression of ABCA1, and enhanced the transportation of intracellular free cholesterol to extracellular space;
4) SPae inhibited the accumulation of AS plaque and reduced the inflammatory response in in vivo mice model.
Conclusion
Through modulating the activities of PPARy and NF-κB and the oxidative stress, and modulating the expressions of SRA and ABCA1and the formation of inflammation during AS, SPae achieves the anti-AS effect.
Background
Compared with patients without diabetes, patients with diabetes mellitus (DM) had significantly increased cardiovascular morbidity and mortality. So far,coronary stent had been widely used for revascularization in acute cardiac events and proved to improved prognosis, with a high success rate and favorable early outcome. The traditional bare-metal stent (BMS) had been initially widely used for treatment of coronary heart disease and had considerable efficacy and safety. However, the long term outcome and restenosis rate has been very discouraging. Recently, sirolimus-eluting stents (SES) had been increasingly performed for treating restenosis after BMS as well as the native coronary narrowing, and made therapeutic progress. Efforts to explore the treatment of coronary heart disease patients with diabetes mellitus at home and abroad has never been interrupted.For coronary arterial disease (CAD) patients with diabetes, the outcome, the efficacy and safety of SES and BMS remain controversial in different clinical trials.
Objective
To compare the efficacy and safety of sirolimus eluting and bare metal stents in CAD patients with diabetes by meta-analysis.
Methods:
The clinical trials were searched according to the detailed inclusion and exclusion criteria, The following key words were used in Chinese,"rapamycin eluting stent;,sirolimus eluting stent, bare metal stent, diabetes, coronary heart disease". The following key words were used in English,"rapamycin eluting stent,sirolimus eluting stent, bare metal stent, diabetes, coronary arterial disease". According to modified Jadad score, two independent researchers included in the study evaluated the quality of each article separately. When consensus can not be reached at the controversial point, the third reviewer were asked and resolved the discrepancies. Grade1-3belongs to low quality and4-7to high quality. If the results of the measurement indexes from the included literatures being dichotomous variables, Odds ratio (OR) and95%confidence intervals (CI) were estimated in each study. Statistical results were expressed in the forest plots and publication bias was evaluated with funnel plots, Begger's and Egger's test.
Results:
Meta-analysis was then performed in a total of1764patients of SEM group and1912patients of BMS group with diabetes from18studies. Authenticity was evaluated for all literatures included in the study according to modified Jadad quality assessment form.10literatures of Western populations were scored between2-7, including two low-quality documents and eight the high-quality literatures,while the8literatures of Chinese populations scored between1-2,belonged to the low-quality literatures. In the research of Western populations, compared with those in bare-metal stent group, the subjects in sirolimus-eluting stent group had reduced risk for target lesion revascularization (OR0.26,95%confidence interval (CI)0.16-0.45), and for major adverse cardiac events (OR0.40,95%CI0.28-0.58). There was no difference for myocardial infarction event (OR0.94,95%CI0.66-1.35)or mortality event (OR1.11,95%CI0.72-1.73). In the research of Chinese populations, compared with those in bare-metal stent group, the subjects in sirolimus-eluting stent group had reduced risk for target lesion revascularization (OR0.30,95%CI0.14,0.62), and for major adverse cardiac events (OR0.25,95%CI0.15-0.42). There was no difference for myocardial infarction event (OR0.64,95%CI0.31-1.31) or mortality event (OR0.62,95%CI0.22-1.76). Subgroup analysis showed significant difference for overall risk of major cardiac events between SES and BMS, when the sample size was<90(OR0.30,95%CI0.19～0.47), when it was randomized control trial (RCT)(OR0.30,95%CI0.22～0.40), or when it was performed in Europeans (OR0.42,95%CI0.32～0.52).
Conclusion:
1、In the research of Chinese and Western populations, target lesion revascularization rate in SEM group was significantly less than that of BMS group.
2、In the research of Chinese and Western populations, incidence of myocardial infarction in SEM group was less than that of BMS group, but the difference was not statistically significant.
3、In the research of Western populations, mortality event in SEM group were more than the BMS group, and in the research of Chinese populations, mortality event rate in SEM group were less than that of BMS group., but the difference was not statistically significant.
4、In the research of Chinese and Western populations, incidence of major cardiac events in SEM group was significantly less than that of BMS group.
Our study confirmed that SES is more effective and safer than BMS in CAD patients with diabetes.
引文
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