Compartmental PKA and Pathological Cardiac Hypertrophy

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Project Summary/Abstract: Pathological cardiac hypertrophy (PCH) is an independent risk factor for lethal ventricular arrhythmias and heart failure. There is an unmet clinical need for more effective therapies to prevent or treat PCH. While PKA activation after sympathetic/β-adrenergic system stimulation is essential for the normal regulation of heart rate and cardiac contractility, persistent activation of sympathetic/β-adrenergic system/protein kinase A (PKA) in cardiovascular diseases such as hypertension leads to PCH and contractile dysfunction. However, it remains unclear how PKA promotes PCH and if manipulating PKA activation can be used to treat or prevent PCH. PKA activity is negatively regulated by endogenous PKA inhibitor peptides (PKI) in the heart. We found for the first time that one of the PKI isoform, PKIα, is concentrated in the nucleus of adult cardiomyocytes and keeps nuclear PKA activation less sensitive to stimulation and activated at a slower rate than cytosolic PKA. Furthermore, pressure overload reduces PKIα expression, especially in the nucleus, and its capability to inhibit PKA. When PKIα is genetically ablated in mice, nuclear PKA activity is enhanced, leading to surprisingly reduced PCH after pressure overload. On the other hand, when myocyte PKA is inhibited by only the PKA inhibition domain of PKIα (PKAi), PCH induced by pressure overload is blunted. Our cultured myocyte study suggest that this PCH reduction is related to cytosolic PKA inhibition. Therefore, we propose that the localization of PKA activation is crucial for its effect on the development of PCH. Depending on the cellular location (compartment) of PKA activation, PKA can either promote or blunt PCH induced by pressure overload. Based on these preliminary studies, we hypothesize that: while cytosolic PKA activation is prohypertrophic, nuclear PKA activation is antihypertrophic; endogenous PKIα exerts inhibition on nuclear PKA activation. We further predict that cytosolic PKA inhibition with enhanced nuclear PKA will be a desired strategy to prevent or treat PCH. We’ll test the hypothesis in three aims: 1) To determine the gene dose-dependent effects and mechanisms of global cardiomyocyte-specific PKA inhibition (PKAi) on cardiac structural and functional remodeling in response to hypertrophic stress. 2) To determine the effects of inhibiting cytosol PKA (with a cytosol-targeted PKAi) on PCH development. 3) To determine the effects of nuclear PKA activation by PKIα knockout or nuclear PKA overexpression or nuclear PKA inhibition on the development of PCH. The accomplishment of the proposed studies will provide novel insights into the roles of compartmental PKA and its regulation by PKIα in the development of PCH. New knowledge generated from this project will shed light into developing novel therapeutic strategy for the prevention and treatment of PCH in patients.