Abstract-Angiotensin II (Ang II) has important actions on the heart via type 1 (AT 1 ) and type 2 (AT 2 ) receptors. The link between AT 1 receptor activation and the hypertrophy of cardiomyocytes is accepted, whereas the contribution of the AT 2 receptor, which reportedly antagonizes the AT 1 receptor, is contentious. This ambiguity is primarily based on in vivo approaches, in which the direct effect of the AT 2 receptor and its modulation of the AT 1 receptor (at the level of the cardiomyocyte) are difficult to establish. In this study, we used adenoviruses encoding AT 1 and AT 2 to coexpress these receptors in isolated cardiomyocytes, allowing a direct examination of the consequence of varying AT 1 /AT 2 stoichiometry on cardiomyocyte hypertrophy. Key Words: angiotensin II Ⅲ hypertrophy Ⅲ myocytes Ⅲ rats Ⅲ receptors L eft ventricular hypertrophy (LVH) is a major independent risk factor for premature death. 1 Extensive experimental and clinical evidence supports a role for the vasoactive hormone angiotensin II (Ang II) in the development of hypertension and the associated cardiomyocyte enlargement, which is a hallmark of LVH. Ang II binds with high affinity to type 1 (AT 1 ) and type 2 (AT 2 ) Ang II receptors, which are 7-transmembrane spanning, G-protein-coupled receptors. 2 AT 1 receptors are well characterized and mediate the established actions of Ang II, including vasoconstriction, aldosterone and vasopressin release, renal sodium reabsorption, increased collagen deposition, cellular proliferation, and, importantly, cardiomyocyte hypertrophy. The role of the AT 2 receptor is less clear, but current theories favor a role in opposing the actions of the AT 1 receptor. 3-7 AT 2 receptors are highly expressed in the fetus; however, after birth, the AT 2 receptor expression decreases to low levels. 2 In normal, adult human and rat hearts, AT 1 and AT 2 receptors are expressed, 8 -10 and they have been shown to be upregulated during cardiovascular pathologies. 8,9 The specific signaling pathways activated via the AT 2 receptor remain poorly resolved, although AT 2 receptors reportedly inhibit AT 1 receptor signaling pathways, such as extracellular signalregulated kinase 1/2 (ERK1/2) mitogen-activated protein kinases (MAPKs), by activating specific tyrosine or serine/ threonine phosphatases. 6,11,12 More recent evidence suggests functional heterodimerization between the AT 1 and AT 2

Abstract-Autophagy has emerged as an important process in the pathogenesis of cardiovascular diseases, but the proximal triggers for autophagy are unknown. Angiotensin II plays a central role in the pathogenesis of cardiac hypertrophy and heart failure. In this study, we used angiotensin II type 1 (AT 1 ) and type 2 (AT 2 ) receptor-expressing adenoviruses in cultured neonatal cardiomyocytes to provide the first demonstration that neonatal cardiomyocyte autophagic activity is differentially modulated by AT 1 and AT 2 receptor subtypes. 4 and its function is less well delineated. Normally present only at low levels in the adult myocardium, AT 2 expression is upregulated in the pathological remodeling heart. 3 AT 2 -mediated cardiovascular responses have been characterized as generally opposing AT 1 -mediated growth effects, but some studies indicate that the AT 2 receptor is also involved in inducing left ventricular hypertrophy. 5,6 We have also shown that the AT 2 receptor can mediate myocyte hypertrophy independent of Ang II in isolated neonatal cardiomyocytes. 7 Thus, the role of the AT 2 receptor remains ambiguous.Autophagy is an intracellular degradation process that involves the destruction of long-lived proteins and organelles. Recently, autophagy has been particularly recognized as important in the turnover of cytoplasmic constituents in the heart. Autophagic activity is commonly increased in the heart under conditions that also involve upregulation of the reninangiotensin system. For example, high levels of autophagy are found in the heart after acute and chronic ischemia, heart failure, and neonatal starvation. 8 There is emerging evidence that pressure overload, a major risk factor for cardiac hypertrophy and heart failure, is associated with an excess of autophagy, which is ultimately maladaptive under such conditions of hemodynamic stress. 9 The proximal triggers for autophagy in the heart are not known.AT 1 receptor activation stimulates protein synthesis and protein turnover in cardiomyocytes. Intracellular protein aggregation is an important precursor event for cardiomyocyte autophagy. 10 Thus, links among activation of the renin-angiotensin system, protein turnover stimulation, and autophagic upregulation may be identified in several pathophysiological myocardial conditions. Therefore, in this study we hypothesized that the AT 1 and AT 2 receptor subtypes play a

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