cAMP/CREB Signaling and Cardiac Function

$477,963P01FY2006HLNIH

Veterans Medical Research Fdn/San Diego, San Diego CA

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Abstract

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

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