ABSTRACT - Heart failure is a multifactorial disease, characterized by ventricular hypertrophy, myocyte death, fibrosis, and contractile dysfunction. Cyclic nucleotide second messengers, cAMP and cGMP, regulate numerous physiological functions and pathological processes in the heart, ranging from short-term muscle contraction/relaxation to long-term structural remodeling. Dysregulated cAMP/cGMP homeostasis has been implicated in various diseases. cAMP/cGMP are NOT freely diffusible. They exist as multiple spatially discrete and functionally distinct cyclic nucleotide “pools”, which is believed to associate with different multi-protein complexes each containing unique cyclases, phosphodiesterases (PDEs), and other signaling molecules. PDEs, by catalyzing the degradation reaction, are essential for maintaining homeostasis, compartmentalization, and specificity of cyclic nucleotide-mediated signaling and functions. Increasing evidence has indicated that alterations in the expression/activation of different PDEs represent causative mechanisms for a number of diseases. PDE10A gene encoded isozymes are able to hydrolyze both cAMP and cGMP in cell-free systems. Under the physiological condition, PDE10A expression is enriched in the striatum of the brain. Most studies to date have focused on neurological diseases, leading to advancing PDE10A inhibitors to clinical trials for schizophrenia. However, the roles of PDE10A in the peripheral systems are still poorly understood. Recently, we have first reported the induction of PDE10A expression in human and mouse failing hearts. Using genetic and pharmacological approaches, we have demonstrated that PDE10A plays a critical role in pressure overload- induced heart failure in mice. However, the cellular and molecular mechanisms remain unclear with respect to the protective effects of PDE10A deficiency/inhibition in the heart. The identity and source of the cyclic nucleotide regulated by PDE10A in CMs remain uncharacterized. Our preliminary data support a hypothesis that PDE10A inhibition uniquely promotes A2AR-D2R heterodimerization and biased activation of D2R/barr2 signaling through potentiating A2AR/cAMP/PKA-mediated phosphorylation of D2R. D2R/baar2 signaling leads to B56d-PP2A activation, HDAC5 nuclear import, and ultimate attenuation of CM hypertrophy and death. To test our hypothesis, we propose two aims: (1) determine the functionsand underlying mechanism of PDE10A in CMs using in vitro cellular models; (2) determine the role of CM-specific PDE10A and A2AR-D2R signaling in cardiac ischemic injury and remodeling in vivo. Our findings will provide the novel insights into the unique sources of cyclic nucleotides, GPCRs, and signaling pathways that are specifically regulated by PDE10A in CMs; as well as advance our understanding the novel roles of D2R signaling in cardiac tissues. Defining the specific cyclic nucleotide signaling modulated by PDE10A may facilitate the development of novel therapeutic strategies through targeting PDE10A in combination with other cyclic nucleotide modulators to achieve additive or synergistic effects with less deleterious side effects.

Project Narrative – Relevance to Public health Heart failure remains a leading cause of mortality in the United States. The underlying molecular mechanisms of pathological cardiac remodeling and dysfunction in heart failure are not fully understood. Our goal is to advance our understanding of the molecular and cellular bases of heart failure, which may lead to the identification of novel therapeutic targets and strategies for treating heart failure. This project is to elucidate the functions and underlying mechanisms of dysregulating cyclic nucleotide phosphodiesterase 10A (PDE10A) expression in pathological cardiac remodeling and dysfunction, particularly from the perspective of revealing the therapeutic potential of PDE10A inhibition in pharmacological intervention of cardiac disorders. Given the clinical trials of PDE10A inhibitors for schizophrenia and Huntington’s disease, PDE10A has been proven to be a safe drug target.