Ang-(1-7), ACE2 and Cardiac Function

七肽血管紧张素-(1-7)[Ang-(1-7)]的血管扩张和降压作用促进了对肾素血管紧张素系统（RAS）生化生理学的更深入研究，并刺激了最近发现的血管紧张素转换酶（ACE）同源物（ACE2），其作为羧肽酶，将血管紧张素II （Ang II）转化为Ang-(1-7)，对ACE抑制剂不敏感。与几种高血压遗传模型的表达有关，并调节心功能。本研究的主要目的是证明ACE2的表达和活性在决定Ang-(1-7)对Ang II在心室收缩力和高血压相关心脏肥厚发展方面的相反作用中起关键作用。这些研究将在血压正常的情况下进行

The vasodilator and antihypertensive effects of the heptapeptide angiotensin-(1-7) [Ang-(1-7)] promoted a more intense investigation of the biochemical physiology of the renin angiotensin system (RAS) and was a stimulus in the recent discovery of an angiotensin converting enzyme (ACE) homolog (ACE2) which acting as a carboxypeptidase, converts angiotensin II (Ang II) into Ang-(1-7), is insensitive to ACE inhibitors, is linked to the expression of several genetics models of hypertension and regulates cardiac function. The primary objective of this proposal will be to show that ACE2 expression and activity plays a critical role in determining the opposing actions of Ang-(1-7) on Ang II in terms of ventrieular contractility and the development of hypertension-related cardiac hypertrophy. These studies will be performed in normotensive Lewis and mRen2.Lewis hypertensive rats. To accomplish these objectives we will: 1)- determine the expression and tissue localization of Ang-(1-7) and ACE2 in the hearts of onrmotensive Lewis and mRen2.Lewis hypertensive rats alone and in relation to the supporting collagen matrix and angiotensin receptors (Specific Aim 1); 2)- characterize the role of cardiac ACE2 and other Ang-(1-7) forming enzymes in contributing to the formation of Ang-(1-7) in the heart versus the systemic circulation (Specific Aim 2); 3) assess the effects of chemical inhibition of ACE2 on the regulation of blood pressure and cardiac function in chronically instrumented normotensive and mRen2.Lewis hypertensive rats (Specific Aim 3); and 4)- employ antisense technology and an adenovirus vector to either inhibit or selectively augment, respectively, the expression of cardiac ACE2 in normotensive Lewis and mRen2.Lewis hypertensive rats to study the effects of these maneuvers on cardiac performance in isolated heart per fusion model (Specific Aim 4). The proposed studies will provide a new understanding of the biochemical physiology of the RAS and the mode of action of therapies that depend upon inhibition of either ACE or Ang II receptor blockade.