ANGIOTENSIN II RECEPTORS AND VSM HYPERSENSITIVITY

描述 （摘自申请人摘要）被广泛研究的机制之一 参与高血压的发展和维持的是 血管紧张素系统 强效血管收缩肽血管紧张素II (AII)它在心血管调节中起着重要作用， 体内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发挥肥大和促有丝分裂作用 细胞 越来越明显的是，VSM细胞的生长是一个 有助于血管阻力增加的重要特征。 两 高胰岛素血症和胰岛素抵抗被认为是易患 血管张力增加，因此，高胰岛素血症可能在 血管壁自发发生结构变化 高血压大鼠（SHR），并感兴趣的是确定是否 高胰岛素血症参与了SHR对VSM的超敏反应。 AII 受体亚型，AT 1和AT 2已被鉴定和表征， 显示AT 1受体介导血管系统中的AII反应。 我们 计划表征高血压前期（4-6周龄）的AT 1受体， 建立高血压（12周龄）年龄匹配的SHR，其血压正常 对照组，Wistar-Kyoto（WKY）大鼠。 我们已经证明胰岛素 上调AII受体，并认为它在AII刺激的 VSM细胞的生长。 我们计划确定蛋白酪氨酸激酶 磷酸化，这被认为是血管 平滑肌（VSM）细胞生长受到刺激，是必不可少的信号 AII刺激的VSM细胞生长的转导，并确定 胰岛素在AT 1受体调节中的作用。 这些研究将 涉及受体结合试验，测量：AT 1的表达 受体mRNA，受体偶联机制，包括IP 3的产生，PKC 活性和细胞内Ca 2+释放，AII刺激的酪氨酸激酶 在VSM中的磷酸化、c-fos、c-myc和c-jun表达和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， 将测定AT 1受体的mRNA稳定性。 最后，一项研究将 研究胰岛素对AT 1受体的上调是否与 上述机制。 我们希望能够深入了解 VSM的超敏反应机制可能与病因有关 原发性高血压 (End摘要）

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)