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

七肽血管紧张素-(1-7)[Ang-(1-7)]的血管扩张和降血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的研究，并刺激了最近发现的血管紧张素转换酶(ACE)同系物(ACE2)，ACE2作为一种羧肽酶，将血管紧张素II(Ang II)转化为Ang-(1-7)，对ACE抑制剂不敏感，与多种高血压遗传模型的表达有关，并调节心脏功能。这项建议的主要目的是证明ACE2的表达和活性在决定Ang-(1-7)对Ang II的相反作用方面发挥关键作用，这些作用涉及到心室收缩能力和高血压相关的心肌肥厚的发展。这些研究将在正常血压下进行。 Lewis和mRen2.Lewis高血压大鼠。为了实现这些目标，我们将：1)确定Ang-(1-7)和ACE2在血压正常的Lewis和mRen2大鼠心脏中的表达和组织定位；Lewis高血压大鼠单独以及与支持胶原基质和血管紧张素受体有关的表达和组织定位(特定目标1)；2)表征心脏ACE2和其他Ang-(1-7)形成酶在促进心脏相对于体循环形成Ang-(1-7)方面的作用(特定目标2)；3)评估化学抑制ACE2对慢性仪器化正常血压和mRen2调节血压和心功能的影响。Lewis高血压大鼠(特定目标3)；和4)-使用 反义技术和腺病毒载体分别抑制或选择性增强正常血压Lewis和mRen2高血压大鼠心脏ACE2的表达，以研究这些操作对心脏每融合模型心功能的影响(特异性目标4)。建议的研究将为RAS的生化生理学和依赖于抑制ACE或Ang II受体阻断的治疗的作用模式提供新的理解。

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.