Mechanisms for Adenylyl Cyclase Effects in the Heart

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Adenylyl cyclase (AC) has long been recognized as a pivotal effector molecule in cardiac myocytes and other cells. In 1998 we showed that the amount of adenylyl cyclase sets a limit on the ability of cardiac myocytes to generate cAMP.1 Subsequent studies showed that AC gene expression has a pronounced favorable effect on cardiovascular function in normal and failing hearts,2-7 including increased global left ventricular (LV) function, increased survival and prevention of deleterious remodeling. Preliminary data from our laboratory suggest that AC expression also is associated with reduced mortality in acute myocardial infarction. Mechanisms explaining these favorable effects of AC on heart function are unknown. The most direct explanation - that the benefits stem from increased intracellular levels of cAMP - is contrary to current dogma in heart failure asserting that inotropic agents that increase cAMP are bad for the heart.8 The absence of unassailable mechanisms for these favorable effects - and the potential for broadened application of AC in cardiovascular therapeutics - mandate a rigorous study of how AC expression effects cardiac structure, function and transcriptional regulation. This proposal is designed to determine mechanisms by which AC affects cardiac function and survival in acute myocardial infarction and heart failure. We propose to use animal models of clinically relevant cardiovascular diseases, unique lines of transgenic mice and methods of gene transfer to discover how AC confers favorable effects on heart function. The use of transgenic mice with targeted deletions of AC type V (ACV) and type VI (ACVi) - the dominant isoforms in mammalian heart - and strategic use of inducible cardiac-specific expression of AC provide novel approaches that will enable us to achieve our goals. Hypotheses: 1. Increased adenylyl cyclase expression in cardiac myocytes will be associated with reduced early mortality after myocardial infarction. 2. Increased adenylyl cyclase expression in cardiac myocytes of failing hearts will be associated with expression of genes that increase contractility. 3. Increased cardiac myocyte adenylyl cyclase content will alter gene expression and protein phosphorylation through cAMP-dependent and cAMP-independent pathways. 4. Elimination of adenylyl cyclase Type V and Type VI will have effects on cardiac function that elucidate their specific functional roles. Targeted deletions of adenylyl cyclase Type VI will have adverse effects on normal and failing hearts.