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.
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