ROLE OF MAPKinases ON MOLECULAR MECHANISUMS OF CARDIOVASCULAR REMODELING

肾素-血管紧张素-醛固酮系统(RAAS)在血压的生理调节和心血管器官损害的病理生理破坏中发挥着重要作用。血管紧张素II(Ang II)是RAAS的主要生物介质。血管紧张素II的病理生理作用是通过血管紧张素II的I型受体介导的，如血管收缩、醛固酮的分泌、肾近端肾单位对钠的重吸收以及细胞的生长和增殖。RAAS抑制剂、血管紧张素转换酶和血管紧张素ⅡI型受体拮抗剂在高血压大鼠模型中起到预防高血压、心肌肥厚、血管硬化和肾小球硬化的作用。此外，这些作用还与抑制转化生长因子-β、I型胶原、II型胶原、纤维连接蛋白的基因表达有关。这些基因的表达是通过激活丝裂原激活的蛋白激酶(ERK和JNK)来刺激血管紧张素ⅡI型受体。血管紧张素转换酶和血管紧张素ⅡI型受体拮抗剂均可抑制ERK和JNK的激活。本研究探讨了细胞凋亡信号调节蛋白1(ASK-1)、ERK、JNK、p38和活化蛋白1(AR 1)在心血管器官损伤中的作用。对Thy-1肾小球肾炎模型进行肾小球转录组分析。ASK-1、ERK、JNK、p38和AP-1与心肌肥厚、血管新生内膜增生和肾小球损害密切相关。这些结果表明，MAP激酶家族有望成为心血管疾病的潜在治疗靶点。

The renin-angiotensin-aldosterone system (RAAS) plays an important role in both the physiological regulation of blood pressure and in the pathophysiological disruption of cardiovascular organ damages. Angiotensin II (Ang II) is the primary biological mediator of the RAAS. Pathophysiological actions of Ang II is mediated by the angiotensin II type I receptor, for examples of, vasoconstriction on vascular smooth muscle, secretion of aldosterone, reabsorption of sodium in the renal proximal nephron, and cell growth and proliferation.Treatments of RAAS inhibitors, angiotensin converting enzyme and Ang II type I receptor antagonist, in hypertensive rat models caused prevention effects of hypertension, cardiac hypertrophy, and vascular sclerosis and glomerular sclerosis. In addition, these effects were associated with suppressive gene expressions of TGF-b, collagen type I, collagen type II, fibronectin. These gene expressions were caused by the stimulation of Ang II type I receptor through the activation of mitogen activated protein kinases (ERK and JNK). Both angiotensin converting enzyme and Ang II type I receptor antagonist inhibited the activation of ERK and JNK.In this study, we investigated the role of apoptosis signal-regulating kinase 1 (ASK-1),ERK,JNK,p38 and activated protein 1 (AR 1) on cardiovascular organ damages. Furthermore, transcriptome analysis of glomerulus was performed in Thy-1 glomerular nephritis model. ASK-1,ERK,JNK,p38 and AP-1 are crossly related to the cardiac hypertrophy, vascular neointimal hyperplasia and glomerular damages. These results suggested that MAP Kinases family is proposed to be a potential therapeutic target for cardiovascular diseases.