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

Ang-(1-7)、ACE2 与心脏功能

• 批准号: 7063095
• 负责人: CARLOS M FERRARIO
• 金额: $ 23.02万
• 依托单位: WAKE FOREST UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-04-01 至 2009-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7063095
• 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) 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) 同系物 (ACE2)，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，与多种高血压遗传模型的表达有关并调节心脏功能。该提案的主要目的是证明 ACE2 表达和活性在确定 Ang-(1-7) 对 Ang II 在心室收缩力和高血压相关心脏肥大的发展方面的相反作用方面发挥着关键作用。这些研究将在血压正常的情况下进行 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 在降血压 Lewis 和 mRen2 心脏中的表达和组织定位。Lewis 高血压大鼠单独以及与支持性胶原基质和血管紧张素受体的关系（具体目标1）； 2)- 描述心脏 ACE2 和其他 Ang-(1-7) 形成酶在心脏中与体循环中促进 Ang-(1-7) 形成的作用（具体目标 2）； 3) 评估 ACE2 化学抑制对长期正常血压和 mRen2.Lewis 高血压大鼠血压和心脏功能调节的影响（具体目标 3）； 4)- 雇用 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中心脏ACE2的表达。Lewis高血压大鼠研究这些操作对离体心脏融合模型中心脏性能的影响（具体目标4） 。拟议的研究将为 RAS 的生化生理学以及依赖于 ACE 或 Ang II 受体阻断的治疗的作用模式提供新的认识。