Cyclic nucleotide phosphodiesterases (PDEs), by catalyzing the breakdown reaction, play essential roles in the regulation of the magnitude, duration, and compartmentation of individual cyclic nucleotide pools. However, little is known about the causal relationship between alterations of PDE expression/activity and cardiac dysfunctions. The objective of this project is to understand the regulation and function of PDE3A isoform in cardiac gene expression and the progression of heart failure. PDE3A is one of the important cAMP-hydrolyzing PDEs in cardiac myocytes. Recently, we found that the expression of PDE3A is downregulated in human and animal failing hearts. Downregulation of PDE3A is associated with myocyte apoptosis through sustained induction of a transcriptional repressor ICER (inducible cAMP early repressor) and thereby inhibition of anti- apoptotic molecule Bcl-2 expression, which provides the molecular mechanism for how chronic angiotensin II (Ang II) and 2-adrenergic receptor (2-AR) stimulation induce myocyte apoptosis. Interestingly, the sustained ICER induction is maintained by a positive feedback mechanism involving the interactions between PDE3A and ICER (referred to PDE3A-ICER feedback loop). Specifically, ICER represses PDE3A gene transcription and PDE3A reduction stimulates cAMP/PKA signaling, leading to ICER upregulation via PKA-dependent stabilization of ICER protein. In addition to the pro-apoptotic effect, our preliminary data show that sustained ICER induction may downregulate a number of other proteins that critically regulate myocyte contractile function and electrophysiology. PDE3A is a key regulator of the positive feedback loop since we demonstrated that preserving PDE3A function terminates the feedback loop and prevents the sustained ICER induction. Therefore, we hypothesize that the PDE3A-ICER feedback loop is a pathogenic mediator of cardiac dysfunction and heart failure, and maintaining PDE3A expression and function will be an attractive approach to block the PDE3A-ICER feedback loop and prevent the progression of heart failure. To test the hypothesis, we propose three aims, Aim 1: Determine the roles and mechanisms of the PDE3A-ICER feedback loop in cardiac myocyte dysfunction;
Aim 2 : Define the molecular mechanisms that stimulate PDE3A gene expression and thereby prevent the PDE3A-ICER positive feedback loop;
Aim 3 : Determine if restoring PDE3A function improves cardiac function in animal models of heart failure. Significance: The findings will provide novel insights into the molecular mechanisms underlying the development of heart failure, and may lead to the identification of novel therapeutic targets for treating heart failure.
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