Protein Kinase A Is a Master Regulator of Physiological and Pathological Cardiac Hypertrophy

The sympathoadrenergic system and its major effector PKA (protein kinase A) are activated to maintain cardiac output coping with physiological or pathological stressors. If and how PKA plays a role in physiological cardiac hypertrophy (CH) and pathological CH (PaCH) are not clear.Transgenic mouse models expressing a PKA inhibition peptide-GFP fusion protein in a cardiac-specific and inducible manner (cPKAi) were used to determine the roles of PKA in physiological CH during postnatal growth or induced by swimming, and in PaCH induced by transaortic constriction (TAC) or augmented Ca2+ influx. Kinase profiling was used to determine cPKAi specificity. Echocardiography was used to determine cardiac morphology and function. Western blotting and immunostaining were used to measure protein abundance and phosphorylation. Protein synthesis was assessed by puromycin incorporation and protein degradation by measuring protein ubiquitination and proteasome activity. Neonatal rat cardiomyocytes (NRCMs) infected with AdGFP or AdPKAi-GFP were used to determine the effects and mechanisms of cPKAi on myocyte hypertrophy. rAAV9.PKA inhibition peptide-GFP was used to treat TAC mice.(1) cPKAi delayed postnatal cardiac growth and blunted exercise-induced physiological CH; (2) PKA was activated in hearts after TAC due to activated sympathoadrenergic system, the loss of endogenous PKIα (PKA inhibitory peptide α), and the stimulation by noncanonical PKA activators; (3) cPKAi ameliorated PaCH induced by TAC and increased Ca2+ influxes and blunted neonatal rat cardiomyocyte hypertrophy by isoproterenol and phenylephrine; (4) cPKAi prevented TAC-induced protein synthesis by inhibiting mTOR signaling through reducing Akt activity, but enhancing inhibitory GSK-3α and GSK-3β signals; (5) cPKAi reduced protein degradation by the ubiquitin-proteasome system via decreasing RPN6 phosphorylation; (6) cPKAi increased the expression of antihypertrophic ANP; (7) cPKAi ameliorated established PaCH and improved animal survival.Cardiomyocyte PKA is a master regulator of physiological CH and PaCH through regulating protein synthesis and degradation. cPKAi can be a novel approach to treat PaCH.