ANGIOTENSIN II RECEPTORS AND VSM HYPERSENSITIVITY

描述 (改编自申请人的摘要)被广泛研究的机制之一 参与高血压的发展和维持的是 肾素-血管紧张素系统。强效血管收缩肽血管紧张素II (AII)在心血管调节中起重要作用的液体 动态平衡和神经内分泌调节已被证明是一种 细胞生长因子对VSM的肥大和促有丝分裂作用 细胞。越来越明显的是，VSM细胞生长是一种 导致血管阻力增加的重要特征。两者都有 高胰岛素血症和胰岛素抵抗被认为是易感因素 血管张力增加，因此，高胰岛素血症可能在 自发性血管壁结构变化的发展 高血压大鼠(SHR)，并有兴趣确定 高胰岛素血症参与了自发性高血压大鼠VSM的超敏反应。所有人 受体亚型AT1和AT2已被鉴定和鉴定 研究表明，AT1受体介导了血管系统中的所有II反应。我们 计划在高血压前期(4-6周)和 已建立的高血压(12周龄)年龄匹配的SHR及其正常血压 对照，Wistar-京都(WKY)大鼠。我们已经证明了胰岛素 上调AII受体，并认为它在AII刺激中发挥作用 VSM细胞的生长。我们计划确定蛋白酪氨酸激酶 磷酸化被认为是血管生成的机制 平滑肌(VSM)细胞的生长受到刺激，是必不可少的信号 转导AII刺激的VSM细胞生长，并确定 胰岛素在AT1受体调节中的作用这些研究将 包括受体结合分析，测量：AT1的表达 受体mRNA，受体偶联机制，包括IP3的产生，PKC AII刺激的酪氨酸激酶活性和细胞内钙释放 VSM中磷酸化、c-fos、c-myc和c-jun的表达及DNA合成 细胞。此外，还研究了胰岛素对基因启动子活性的影响以及对基因启动子活性的影响。 AT1受体的信使核糖核酸稳定性将测定。最后，将进行一项研究 观察胰岛素上调AT1受体是否偶联 以上提到的机制。我们希望能深入了解 室上性心动过敏症的发病机制 高血压病。(摘要结束)

DESCRIPTION (Adapted from applicant's abstract) One of the widely studied mechanisms involved in the development and maintenance of hypertension is the renin-angiotensin system. The potent vasoconstrictor peptide angiotensin II (AII) which plays an important role in cardiovascular regulation, fluid homeostasis and neuroendocrine regulation has been shown to act as a cellular growth factor, exerting hypertrophic and mitogenic effects on VSM cells. It is becoming increasingly evident that VSM cell growth is an important feature contributing to the increase in vascular resistance. Both hyperinsulinemia and insulin resistance have been claimed to predispose increased vascular tone, and therefore, hyperinsulinemia may play a role in the development of structural changes in the vessel wall spontaneously hypertensive rat (SHR) and it is of interest to determine whether hyperinsulinemia is involved in the hypersensitivity of VSM in SHR. AII receptor subtypes, AT1 and AT2 have been identified and characterized and it was shown that AT1 receptors mediate AII responses in the vasculature. We plan to characterize the AT1 receptors in prehypertensive (4-6 week-old) and established hypertensive (12 week-old) age-matched SHR, and its normotensive control, Wistar-Kyoto (WKY) rat. We have demonstrated that insulin up-regulates AII-receptors and believe that it play a role in AII-stimulated growth of VSM cells. We plan to determine whether protein tyrosine kinase phosphorylation which is suggested to be the mechanisms by which vascular smooth muscle (VSM) cell growth is stimulated, is essential for the signal transduction of AII-stimulated growth of VSM cells, and to determine the role of insulin in the regulation of AT1 receptors. The studies will involve receptor binding assays, the measurement of: the expression of AT1 receptor mRNA, receptor coupling mechanisms including IP3 production, PKC activity and intracellular Ca2+ release, AII-stimulated tyrosine kinase phosphorylation, c-fos, c-myc, and c-jun expression and DNA synthesis in VSM cells. Also, the effect of insulin of the gene promoter activity and the mRNA stability of AT1-receptor will be determined. Finally, a study will be done to see whether the up-regulation of AT1-receptors by insulin is coupled to the mechanisms mentioned above. We hope to gain some insight into the mechanisms of hypersensitivity of VSM which may be involved in the etiology of essential hypertension. (End of Abstract)