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Gene regulation and biophysiological significance of angiotensin type 2 receptor

血管紧张素2型受体的基因调控及其生物生理意义

基本信息

批准号：
09470175
负责人：
MATSUBARA Hiroaki
金额：
$ 8.45万
依托单位：
Kansai Medical University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
1997
资助国家：
日本
起止时间：
1997 至 1998
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-09470175/
关键词：
angiotensin II angiotensin II receptor angiotensin AT2 receptor angiotensin AT1 receptor AT1受容体 AT2受容体

项目摘要

The receptors for angiotensin (Ang) II are classified into Iwo subtypes (AT1-R and AT2-R) by the discovery of non-peptidic ligands and AT1-R mediates most of the cardiovascular actions of Ang II.AT2-R is expressed at very high levels in the developing fetus, whereas in the adult its expression in the cardiovascular system is very low. The expression of AP2-R can be modulated by pathological states associated with tissue remodeling or inflammation. In failing hearts or neointima formation after vascular injury, AT2-R is re-expressed in cells proliferating in interstitial regions or neointima and exerts an inhibitory effect on Ang II-induced mitogen signals or synthesis of extracellular matrix proteins, resulting in attenuation of the tissue remodeling. An extreme way of cell growth inhibition directs cells into programmed cell death, and its process initiated by withdrawal of growth factors is also enhanced by AT2-R.Cardiac myocyte- or vascular smooth muscle-specific overexpression mice of AT2-R display an inhibitory effect on Ang II-induced chronotropic or pressor actions, suggesting the role of AT2-R on the activity of cardiac pacemaker cells or maintenance of vascular resistance. AT2-R also activates the kinin/nitric oxide/cGMP system in the cardiovascular and renal system, resulting in the AT2-R-mediated cardioprotection, vasodilation and pressure nairiuresis. These effects transmitted by AT2-R are mainly exerted by stimulation of protein tyrosine or serine/threonine phosphatases in Gi-protein dependent manner. The expression level of AT2-R is much higher in human hearts than in those of rodents, and the AT2-R-mediated actions are likely enhanced, especially by clinical application of AT1-R antagonists.

血管紧张素Ⅱ（Angiotensin，Ang）Ⅱ受体通过非肽配体的发现分为伊沃亚型（AT 1-R和AT 2-R），AT 1-R介导Ang Ⅱ的大部分心血管作用，AT 2-R在发育中的胎儿中表达水平很高，而在成人心血管系统中表达水平很低。AP 2-R的表达可以通过与组织重塑或炎症相关的病理状态来调节。在心力衰竭或血管损伤后新生内膜形成中，AT 2-R在间质区或新生内膜中增殖的细胞中重新表达，并对Ang II诱导的有丝分裂原信号或细胞外基质蛋白的合成产生抑制作用，导致组织重塑减弱。细胞生长抑制的一种极端的方式直接细胞进入程序性细胞死亡，其过程中启动的生长因子的撤回也增强了AT 2-R。心肌细胞或血管平滑肌特异性过表达小鼠的AT 2-R显示抑制作用，血管紧张素II诱导的变时性或升压作用，这表明心脏起搏细胞的活性或维持血管阻力的作用AT 2-R。AT 2-R还激活心血管和肾脏系统中的激肽/一氧化氮/cGMP系统，导致AT 2-R介导的心脏保护、血管舒张和压力性尿失禁。AT 2-R的这种作用主要是通过刺激蛋白酪氨酸或丝氨酸/苏氨酸磷酸酶来实现的，依赖于Gi蛋白。AT 2-R在人心脏中的表达水平远高于啮齿类动物，AT 2-R介导的作用可能会增强，特别是通过临床应用AT 1-R拮抗剂。