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

Ang-(1-7)、ACE2 与心脏功能

• 批准号: 7218010
• 负责人: CARLOS M FERRARIO
• 金额: $ 23.5万
• 依托单位: WAKE FOREST UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-04-01 至 2009-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7218010
• 关键词: ACE inhibitors; angiotensin II; angiotensins; antisense nucleic acid; blood circulation; enzyme mechanism; genetically modified animals; heart circulation; heart function; hypertension; isolation perfusion; isozymes; laboratory rat; organ culture; peptide hormone metabolism; peptidyl dipeptidase A; protein localization; transfection /expression vector

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.

七肽血管紧张素-（1-7）[Ang-（1 - 7）]的血管扩张和抗高血压作用促进了对肾素血管紧张素系统（RAS）的生化生理学的更深入的研究，并且是最近发现的血管紧张素转换酶（ACE）同系物（ACE 2）的刺激因素，ACE 2作为羧肽酶起作用，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相关，并调节心脏功能。本研究的主要目的是证明ACE 2的表达和活性在决定Ang-（1-7）对Ang II在心室收缩性和高血压相关性心肌肥大的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 刘易斯和mRen 2.刘易斯高血压大鼠。为了实现这些目标，我们将：1）确定Ang-（1-7）和ACE 2在非高血压刘易斯和mRen 2大鼠心脏中的表达和组织定位。刘易斯高血压大鼠单独和与支持胶原基质和血管紧张素受体相关（具体目标1）; 2）-表征心脏ACE 2和其他Ang-（1-7）形成酶在促进Ang-（1-7）形成中的作用3）评估ACE 2的化学抑制对慢性仪器正常血压大鼠和mRen2.Lewis高血压大鼠中血压和心脏功能调节的影响（具体目的3）;和4）采用 反义技术和腺病毒载体分别抑制或选择性增加正常血压刘易斯和mRen 2.刘易斯高血压大鼠中心脏ACE 2的表达，以研究这些操作对分离的心脏灌注模型中心脏性能的影响（具体目标4）。拟议的研究将提供一个新的理解的生化生理学的RAS和治疗的作用方式，依赖于抑制ACE或血管紧张素II受体阻滞剂。