PRKAR1A deficiency delays postnatal heart growth

Primary author: Yuening Liu
Faculty sponsor: Zhaokang Cheng

Primary college/unit: College of Pharmacy and Pharmaceutical Sciences
Campus: Spokane


Aims: Protein kinase A (PKA) activity is pivotal for functioning of the human heart, and its dysregulation has been implicated in cardiac pathologies. PKA regulatory subunit 1a (R1a, encoded by the PRKAR1A gene) is highly expressed in the heart, and controls PKA kinase activity. Patients with PRKAR1A mutations are often diagnosed with Carney complex (CNC) in young adults, and may die prematurely from cardiac complications such as heart failure. However, no cardiac defect has been reported in adult animal models of PRKAR1A deficiency.
Methods and Results: To investigate the impact of PRKAR1A deficiency, we generated cardiac-specific PRKAR1A heterozygous knockout mice by breeding the floxed PRKAR1A mice with the Mlc2v-Cre mice. We also studied a cohort of young CNC patients with PRKAR1A mutations or deletions. Ablation of the PRKAR1A gene in mice increased cardiac PKA activity, reduced heart weight and cardiomyocyte size without altering contractile function at 3 months of age. Importantly, left ventricular mass was reduced in young patients diagnosed with CNC. Cardiomyocyte hypertrophy in response to activation of the a1-adrenergic receptor, which is necessary for heart growth after birth, was completely abolished by silencing of PRKAR1A, or stimulation with the PKA activator forskolin. Mechanistically, depletion of PRKAR1A provoked PKA-dependent phosphorylation of the mitochondrial fission protein Drp1 at S637, leading to suppression of mitochondrial fission and inhibition of cardiomyocyte hypertrophy.

Conclusions: PRKAR1A deficiency impedes postnatal myocardial development and physiological hypertrophy through modulation of mitochondrial dynamics. These findings provide a potential novel mechanism for the cardiac manifestations associated with CNC.