氯沙坦逆转心室重构作用及机制的实验研究
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摘要
心室重构（Ventricular remodeling, VR）指在各种内外因素作用下引起左心室心肌原有结构重排，伴有左室重量增加及心室结构发生改变等[1]，包括心肌（细胞）肥大、间质细胞（心肌成纤维细胞，Cardiac fibroblast，CFb）增殖、胶原纤维组织增生等。心肌纤维化引起的左心室重构（LVR）指左心室几何形状发生改变、体积和重量增加。VR常继发于高血压病、冠心病、心肌病及重症心肌炎等心血管疾病，随心室重构的发生和发展，心律失常、心力衰竭及猝死等危险因素的发生率也随之提高，因此及早使用药物控制和逆转心肌肥大、控制左室重构是目前心血管领域中重要的研究内容之一[2]，研究逆转或防治VR的药物具有十分重要的理论价值[3]。
近年来的研究表明循环和局部的RAAS激活是VR的主要病理生理学机制。VR发生后，肾素-血管紧张素-醛固酮系统（RASS）被激活，血管紧张素Ⅱ（Ang Ⅱ）通过增加心肌收缩力、刺激心肌细胞肥大，使心肌间质组织如纤维结缔组织增生，对心梗后VR的发生发展起着重要作用[4]。血管紧张素转换酶抑制剂（Angiotensin converting enzymeinhibitor, ACEI）已广泛应用于临床，此类药物能抑制VR的发展并改善预后，已被临床所证实[5，6]。Ang Ⅱ受体拮抗剂（Angiotensin Ⅱ receptor blocker, AT_1R blocker）是一种新的拮抗RAAS系统的药物，具有较ACEI更广泛的临床用途和潜在作用，在VR防治中的作用一直是心血管领域研究的热点之一，AngⅡ受体拮抗剂对VR作用及研究可望为VR的防治提供一种新型的药物。
氯沙坦（losartan，Lor）是非肽类的血管紧张素Ⅱ的I型受体拮抗剂，能特异性阻滞多种组织中的血管紧张素Ⅱ与AT_1受体部位的结合，从而阻断血管紧张素Ⅱ对心血管系统的作用，且不依赖于血管紧张素Ⅱ的合成通路。氯沙坦与AT_1的亲合力是AT2的3000倍，且不影响血管紧张素转化酶活性或血管紧张素Ⅱ受体的其他亚型[7]。目前该类药物主要应用治疗高血压、充血性心力衰竭、左心室肥厚、肾脏疾病等心血管疾病[8]，对其逆转心室重构的研究近年来报道很多，但逆转作用机制尚未十分明确，尤其是对分子生物学及信号转导方面机制缺乏系统研究。因此本实验通过以心肌细胞和心肌成纤维细胞（CFb）作为靶细胞，从在体和离体两个方面观察氯沙坦（Lor）逆转心室重构作用及作用的分子生物学和信号转导机制，旨在阐明心室重构发生机制和药物作用主要靶点。具体研究内容为：1．异丙肾上腺素（Iso）诱导心室重构（VR）模型，观察Lor对VR影响；检测心肌组织中羟脯氨酸含量；通过HE染色、Masson特染、透射电镜、免疫组织化学染色和Western blot方法观察Lor对心肌形态学和转化生长因子-β_1（TGF-β_1）及磷酸化蛋白激酶C（p-PKCα）表达的影响。结果表明：Lor能明显抑制Iso诱导的心肌肥厚；降低胶原纤维含量；降低羟脯氨酸含量；减少心肌组织中TGF-β_1蛋白和p-PKCα蛋白的表达。2．体外培养CFb细胞，血管紧张素Ⅱ（Ang Ⅱ）诱导其增殖。采用MTT、流式细胞仪观察Lor对细胞增殖和细胞周期的影响；羟脯氨酸法检测CFb中胶原蛋白含量；Westernblot分析Lor对细胞周期蛋白依赖性激酶抑制因子（CDKI）p27~(kip1)蛋白表达的影响。结果表明：Lor能够明显抑制CFb增殖，使细胞周期阻滞于G_0/G_1期；增加p27~(kip1)蛋白的表达，且呈剂量依赖性。3．体外培养CFb细胞，血管紧张素Ⅱ（Ang Ⅱ）诱导其增殖，Westernblotting法观察Lor对p-PKCα和TGF-β_1表达的影响。结果表明：Lor能显著降低p-PKCα和TGF-β_1的蛋白表达，通过降低p-PKCα的信号蛋白表达从而减少TGF-β_1的含量最终起到抗心室重构作用。
Ventricular remodeling(VR) is changed ventricular structure, which includes hypertro-phic cardiomyocytes,interstitial cell (cardiofibroblasts, CFb) proliferation and collagen tissuehyperplasia.LVR induced by cardiac fibrosis means geometric variation of left ventricle,thatis the increase of cardiac volume and mass. It can be classified by elevated collagen volumefraction (CVF) than normal tissues.
VR is triggered by collagen anabolism and catabolism balance disorders in Macroscopicview. The occurrence of VR is related to many factors,briefly, its formation mechanism andadjusting mechanisms are more complex, activation of neuroendocrine system is one of themain leading mechanisms of VR deterioration.Studies show that in VR caused by manyfactors, the RAAS system plays an important role, which led to angiotensin II that is animportant factor in the increase in myocardial collagen, AngII binds with AT_1receptor andactivate PKC, MAPK transduction pathway, transcription factors, promoting myocardial celland CFb to autocrine and paracrine many fiber growth factors, such as ET-1,、TGF-β1,、CTGF etc.
Losartan (Losartan, Lor) reverses ventricular remodeling and myocardial fibrosis whichhave been confirmed, but its mechanism especially molecular biology and signal transductionmechanism is not completely clear. from the in vivo and in vitro two aspects This topic aimsto explore the effect of Lor on VR and the detailed mechanism, designing to elucidate itsmechanisms for reversal of VR, the major targets for drug intervention, the drug in the furtherclinical application and development of new anti-VR drugs to lay the foundation.The mainresearch steps are as follows:1the application of Iso induced rat model of VR, which wasobserved after the administration of Lor's influence on VR; The histopathology techniques was adopted through HE、Masson、TE、IH staining, Western blot etc.to observe themorphology of the rat, myocardial hypertrophy index and TGF-β_1, p-PKCα expression underLor intervention.The results showed that Lor markedly inhibited Iso induced VR phenomenon;reduced the synthesis of collagen hydroxyproline content; reduced o p-PKCα and TGF-β1protein expression. in myocardial tissue.2CFb were cultured in vitro, the Ang Ⅱ-inducedproliferation of CFb.Using an inverted microscope, MTT and flow cytometer to observe theEffect of losartan on cell proliferation and cell cycle.Western blot for Lor on CFb p27kip1Protein Expression in rats.The results showed that: Lor can inhibit the proliferation of CFb,cell cycle arrested in G0/G1phase; increased cyclin dependent kinase inhibitor (CDKI) on theexpression of p27kip1in a dose-dependent manner.3CFb cells were cultured in vitro, theexpression of p-PKCα and the expression of TGF-β1were observed in Western blotdetection for Lor. The results showed that: Lor can inhibit signal transduction molecules ofp-PKCα, p-PKCα protein activity; down-regulate TGF-β_1expression.Indicating that the Lorantagonistic effect of VR by decreasing p-PKCα activity so as to reduce the expression ofTGF-β1.
近年来的研究表明循环和局部的RAAS激活是VR的主要病理生理学机制。VR发生后，肾素-血管紧张素-醛固酮系统（RASS）被激活，血管紧张素Ⅱ（Ang Ⅱ）通过增加心肌收缩力、刺激心肌细胞肥大，使心肌间质组织如纤维结缔组织增生，对心梗后VR的发生发展起着重要作用[4]。血管紧张素转换酶抑制剂（Angiotensin converting enzymeinhibitor, ACEI）已广泛应用于临床，此类药物能抑制VR的发展并改善预后，已被临床所证实[5，6]。Ang Ⅱ受体拮抗剂（Angiotensin Ⅱ receptor blocker, AT_1R blocker）是一种新的拮抗RAAS系统的药物，具有较ACEI更广泛的临床用途和潜在作用，在VR防治中的作用一直是心血管领域研究的热点之一，AngⅡ受体拮抗剂对VR作用及研究可望为VR的防治提供一种新型的药物。
氯沙坦（losartan，Lor）是非肽类的血管紧张素Ⅱ的I型受体拮抗剂，能特异性阻滞多种组织中的血管紧张素Ⅱ与AT_1受体部位的结合，从而阻断血管紧张素Ⅱ对心血管系统的作用，且不依赖于血管紧张素Ⅱ的合成通路。氯沙坦与AT_1的亲合力是AT2的3000倍，且不影响血管紧张素转化酶活性或血管紧张素Ⅱ受体的其他亚型[7]。目前该类药物主要应用治疗高血压、充血性心力衰竭、左心室肥厚、肾脏疾病等心血管疾病[8]，对其逆转心室重构的研究近年来报道很多，但逆转作用机制尚未十分明确，尤其是对分子生物学及信号转导方面机制缺乏系统研究。因此本实验通过以心肌细胞和心肌成纤维细胞（CFb）作为靶细胞，从在体和离体两个方面观察氯沙坦（Lor）逆转心室重构作用及作用的分子生物学和信号转导机制，旨在阐明心室重构发生机制和药物作用主要靶点。具体研究内容为：1．异丙肾上腺素（Iso）诱导心室重构（VR）模型，观察Lor对VR影响；检测心肌组织中羟脯氨酸含量；通过HE染色、Masson特染、透射电镜、免疫组织化学染色和Western blot方法观察Lor对心肌形态学和转化生长因子-β_1（TGF-β_1）及磷酸化蛋白激酶C（p-PKCα）表达的影响。结果表明：Lor能明显抑制Iso诱导的心肌肥厚；降低胶原纤维含量；降低羟脯氨酸含量；减少心肌组织中TGF-β_1蛋白和p-PKCα蛋白的表达。2．体外培养CFb细胞，血管紧张素Ⅱ（Ang Ⅱ）诱导其增殖。采用MTT、流式细胞仪观察Lor对细胞增殖和细胞周期的影响；羟脯氨酸法检测CFb中胶原蛋白含量；Westernblot分析Lor对细胞周期蛋白依赖性激酶抑制因子（CDKI）p27~(kip1)蛋白表达的影响。结果表明：Lor能够明显抑制CFb增殖，使细胞周期阻滞于G_0/G_1期；增加p27~(kip1)蛋白的表达，且呈剂量依赖性。3．体外培养CFb细胞，血管紧张素Ⅱ（Ang Ⅱ）诱导其增殖，Westernblotting法观察Lor对p-PKCα和TGF-β_1表达的影响。结果表明：Lor能显著降低p-PKCα和TGF-β_1的蛋白表达，通过降低p-PKCα的信号蛋白表达从而减少TGF-β_1的含量最终起到抗心室重构作用。
Ventricular remodeling(VR) is changed ventricular structure, which includes hypertro-phic cardiomyocytes,interstitial cell (cardiofibroblasts, CFb) proliferation and collagen tissuehyperplasia.LVR induced by cardiac fibrosis means geometric variation of left ventricle,thatis the increase of cardiac volume and mass. It can be classified by elevated collagen volumefraction (CVF) than normal tissues.
VR is triggered by collagen anabolism and catabolism balance disorders in Macroscopicview. The occurrence of VR is related to many factors,briefly, its formation mechanism andadjusting mechanisms are more complex, activation of neuroendocrine system is one of themain leading mechanisms of VR deterioration.Studies show that in VR caused by manyfactors, the RAAS system plays an important role, which led to angiotensin II that is animportant factor in the increase in myocardial collagen, AngII binds with AT_1receptor andactivate PKC, MAPK transduction pathway, transcription factors, promoting myocardial celland CFb to autocrine and paracrine many fiber growth factors, such as ET-1,、TGF-β1,、CTGF etc.
Losartan (Losartan, Lor) reverses ventricular remodeling and myocardial fibrosis whichhave been confirmed, but its mechanism especially molecular biology and signal transductionmechanism is not completely clear. from the in vivo and in vitro two aspects This topic aimsto explore the effect of Lor on VR and the detailed mechanism, designing to elucidate itsmechanisms for reversal of VR, the major targets for drug intervention, the drug in the furtherclinical application and development of new anti-VR drugs to lay the foundation.The mainresearch steps are as follows:1the application of Iso induced rat model of VR, which wasobserved after the administration of Lor's influence on VR; The histopathology techniques was adopted through HE、Masson、TE、IH staining, Western blot etc.to observe themorphology of the rat, myocardial hypertrophy index and TGF-β_1, p-PKCα expression underLor intervention.The results showed that Lor markedly inhibited Iso induced VR phenomenon;reduced the synthesis of collagen hydroxyproline content; reduced o p-PKCα and TGF-β1protein expression. in myocardial tissue.2CFb were cultured in vitro, the Ang Ⅱ-inducedproliferation of CFb.Using an inverted microscope, MTT and flow cytometer to observe theEffect of losartan on cell proliferation and cell cycle.Western blot for Lor on CFb p27kip1Protein Expression in rats.The results showed that: Lor can inhibit the proliferation of CFb,cell cycle arrested in G0/G1phase; increased cyclin dependent kinase inhibitor (CDKI) on theexpression of p27kip1in a dose-dependent manner.3CFb cells were cultured in vitro, theexpression of p-PKCα and the expression of TGF-β1were observed in Western blotdetection for Lor. The results showed that: Lor can inhibit signal transduction molecules ofp-PKCα, p-PKCα protein activity; down-regulate TGF-β_1expression.Indicating that the Lorantagonistic effect of VR by decreasing p-PKCα activity so as to reduce the expression ofTGF-β1.
引文
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