Adenylyl cyclase regulation and heart failure

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The overriding goal of this Unit is to provide a rationale and an initial test of what we believe may be a new and potentially useful approach for the treatment of heart failure. In the past 5 years we have shown that expression of the catalyst of adenylyl cyclase (AC) is the key limiting component in the generation of cyclic AMP by beta-adrenergic receptor (betaAR) activation. Thus, modulating expression of Ac is a rational strategy for regulating cardiac responsiveness. We have tested the utility of over-expression of AC/VI, a predominant AC isoform in mammalian cardiac myocytes, as a means to increase cardiac responsiveness to catecholamine stimulation. We have demonstrated that this strategy is a highly effective means to increase intracellular cAMP and cardiac function in response to catecholamine stimulation. Over-expressing AC does not alter transmembrane signaling except when receptors are activated, in distinction with receptor/G protein over-expression, which yield continuous activation and the detrimental consequences. Preliminary experiments indicate that expressing AC in the background of cardiomyopathy improves cardiac function and adrenergic responsiveness, These data indicate that cardiac over-expression of AC may be a safe effective means to treat heart failure. We propose four Specific Aims, each of a hypothesis-testing nature, as follows: 1) To test the hypothesis that increased AN/VI expression provides relative betaAR -selective amplification of transmembrane signaling; 2) To test the hypothesis that compartmentation of AC/VI provides betaAR-selective amplification of transmembrane signaling; 3) To test the hypothesis that cardiac over-expression of AC/VI improves cardiac function and responsiveness in murine dilated cardiomyopathy; 4) To test the hypothesis that cardiac over-expression of AC/VI improves cardiac function of betaAR responsiveness in a large animal model of heart failure.