Abstract MP166: PRKAR1A Deficiency Abrogates Cardiac Hypertrophy Through Inhibition of Mitochondrial Fission

Protein kinase A (PKA) is pivotal for cardiac function of human heart, and its dysregulation is involved with various cardiac pathologies. PKA regulatory subunit 1α (R1α, encoded by PRKAR1A gene) controls PKA kinase activity by sequestering the PKA catalytic subunits. Patients with PRKAR1A mutations are often diagnosed with Carney complex (CNC) and may die prematurely from cardiac complications such as heart failure. However, it remains unknown whether PRKAR1A deficiency interferes with normal heart growth during postnatal development. Here, we show that left ventricular mass is reduced in young CNC patients with PRKAR1A mutations or deletions. To investigate the impact of PRKAR1A deficiency on heart growth, we generated cardiac-specific PRKAR1A heterozygous knockout mice. Ablation of the PRKAR1A gene in mice increased cardiac PKA activity, reduced heart weight to body weight ratio and cardiomyocyte size without altering contractile function. Cardiomyocyte hypertrophy in response to activation of the α1-adrenergic receptor, was completely abolished by silencing of PRKAR1A . Mechanistically, depletion of PRKAR1A provoked PKA-dependent phosphorylation of the mitochondrial fission protein Drp1 at S637, resulting in impaired mitochondrial fission and diminished cardiomyocyte hypertrophy. In conclusion, PRKAR1A deficiency abrogates cardiac hypertrophy during postnatal development, likely through inhibiting Drp1-mediated mitochondrial fission. Our study provides novel mechanistic insights regarding the cardiac mortality associated with CNC.