The second messenger cAMP appears critical for maintenance of cardiac function; intracellular cAMP? accumulation is typically reduced in congestive heart failure (CHF). Increasing cellular cAMP levels in heart? by cardiac-directed expression of adenyl cyclase type VI (ACvi) improves cardiac performance and survival? in animal models of CHF. In contrast, treatment with beta-adrenergic receptor (PAR) agonists increases? mortality in CHF patients. Mechanisms explaining the salutary effects of ACVI are now being addressed, but? little is known about how ACvi expression may influence transcriptional regulation in cardiac myocytes and? other cells in the heart. Cyclic AMP has been shown to stimulate cellular gene expression via the PKA-mediated? phosphorylation of the transcription factor cAMP Response Element Binding protein (CREB) at? Ser133, a modification that promotes recruitment of the coactivator CREB Binding Protein (CBP) to the? promoter. Additionally, cAMP triggers nuclear entry of the latent cytoplasmic CREB coactivator, Transducer? of Regulated CREB 2 (TORC2), which enhances target gene expression via a direct interaction with CREB on? relevant promoters. Supporting a role for CREB in mediating the effects of cAMP on cardiac function,? transgenic mice expressing a phosphorylation defective Ser133Ala CREB polypeptide in heart exhibit dilated? cardiomyopathy. Whether and by what mechanism CREB, CBP, and TORC2 mediate the protective effects? of ACvi on cardiac function, however, is unclear.? The overall goals of this Proposal are:? 1. To test whether CREB mediates the salutary effects of ACVI on cardiac function and cardiac myocyte? gene expression.? 2. To test the role of the CREB:TORC2 pathway in this process.
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