Ang II-Induced Hypertension: Role of AT2 in End Organ Damage

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Hypertension and cardiac hypertrophy are major risk factors for progression of cardiac dysfunction and development of congestive heart failure (CHF). Activation of the renin-angiotensin system, which leads to release of angiotensin II (Ang II), plays an important role in these pathological processes. Two major types of Ang II receptors, ATi and AT2, have been identified. The detrimental cardiac effects of Ang II are known to be mediated by activation of AT-i, since suppression of ATi with angiotensin II type 1 receptor antagonists (ATr ant) improves cardiac function, regresses left ventricular remodeling and prolongs survival in patients with HF. We and others have demonstrated that the effects of ATrant are mediated in part by activation of AT2. It has also been shown that activation of AT2 stimulates kinin release; however, the exact mechanism(s) involved is not well known. Nor do we know whether the cardioprotective effect of AT2 is due in part to a direct interaction with kinin B! and/or B2 receptors. Thus we propose to test the general hypothesis that chronic activation of AT2 causes kinin release by increasing kininogenase activity, includingtissue andplasma kallikrein. In addition to kinin release, activation ofAT2 potentiates the kallikrein-kinin system (KKS)by decreasing angiotensin-converting enzyme (ACE) and/or forming heterodimers with the B2 or B1 kinin receptors, leading to release of NO/cGMP and cardiovascular protection. We propose to use a combination of physiological, molecular, and pharmacological approaches and several lines of bioengineered mice to test this hypothesis. In Aim I, we will test the hypothesis that the AT2-induced increase in kinins is due to a) increased tissue kallikrein (TK)expression; b) increased kininogenase activity by activation of tissue prekallikrein to kallikrein; and c) activation of plasma prekallikrein via prolylcarboxypeptidase (PRCP), a known endothelial membrane-bound plasma prekallikrein activator. In Aim II, we will test the hypothesis that the cardiovascular protective effect of AT^ant is mediated in part by AT2-induced potentiation of kinins due to decreased ACE and/or a direct interaction with B2 due to heterodimerization. In Aim III, we will test the hypothesis that increased expression of AT2 and/or B, protects the heart from Ang ll-induced hypertension and cardiac remodeling post-Mi and contributes to the therapeutic effect of ATrant. In Aim IV, we will test the hypothesis that overexpression of AT2 in the vasculature is protective via release of kinins and NO, whereas high-level overexpression in CMs (exceeding AT! expression) is detrimental due to 1) increased kinins that act directly on CMs in an autocrine fashion, contributing to CM hypertrophy; and 2) AT2 interaction with or initiation of signaling events similar to AT^ activation. We believe these studies will enhance our understanding of the physiological and pathophysiological role of AT2 and how it interacts with the kallikrein-kinin system and leads to cardioprotection, as well as facilitate the development of better therapeutic strategies for hypertension and ischemic heart disease. Abbreviations: Ang II = angiotensin II; AT, and AT2 = angiotensin type 1 and type 2 receptors; ACE = angiotensin-converting enzyme; ant = antagonist; BK = bradykinin; B2 = B2 kinin receptors; BNP = brain natriuretic peptide; CHF = congestive heart failure; cGMP = guanosine 3',5'cyclic monophosphate; CMs = cardiomyocytes; COX-2 = cyclooxygenase-2; ECs = endothelial cells; EOD = end organ damage; ERK = extracellular signal-regulated kinase; HMWK = high-molecular weight kininogen; KKS = kallikrein-kinin system; LMWK = low-molecular-weight kininogen; LV = left ventricle; MAPK = mitogen-activated protein kinase; Ml = myocardial infarction; NO = nitric oxide; NOS = nitric oxide synthase; PGE2 = prostaglandin E2; PK = plasma kallikrein; PKC = protein kinase C; PLA2 = phospholipase A2; PTP = protein tyrosine phosphatase; PP2A = protein phosphatase-2A; PRCP = prolylcarboxypeptidase; RAS = renin-angiotensin system;Tg = transgenic; TK = tissue kallikrein; -/- = gene knockout. PHS 398/2590 (Rev.09/04, Reissued4/2006) Page197 Continuation Format Page Principal Investigator/Program Director (Last, First, Middle): Yang, Xiao-Ping, M.D./CarreterO,Oscar A., M.D. A.