cAMP-Dependent Protein Kinase (PKA) Signaling is Impaired in the Diabetic Heart [Signal Transduction]

October 14th, 2015 by Bockus, L. B., Humphries, K. M.

Diabetes mellitus causes cardiac dysfunction and heart failure that is associated with metabolic abnormalities and autonomic impairment. Autonomic control of ventricular function occurs through regulation of cAMP-dependent protein kinase (PKA). The diabetic heart has suppressed β-adrenergic responsiveness, partly attributable to receptor changes, yet little is known about how PKA signaling is directly affected. Controls and streptozotocin-induced diabetic mice were therefore administered 8Br-cAMP acutely to activate PKA in a receptor-independent manner and cardiac hemodynamic function and PKA signaling were evaluated. In response to 8Br-cAMP treatment, diabetic mice had impaired inotropic and lusitropic responses thus demonstrating postreceptor defects. This impaired signaling was mediated by reduced PKA activity and PKA catalytic subunit content in the cytoplasm and myofilaments. Compartment specific loss of PKA was reflected by reduced phosphorylation of discrete substrates. In response to 8Br-cAMP treatment, the glycolytic activator, PFK-2, was robustly phosphorylated in control animals but not diabetics. Control adult cardiomyocytes cultured in lipid-supplemented media developed remarkably similar changes in PKA signaling, suggesting lipotoxicity is a major contributor to diabetes induced β-adrenergic signaling dysfunction. This work demonstrates PKA signaling responds to metabolic conditions and suggests that treating hyperlipidemia is vital for proper cardiac signaling and function.