Dilated cardiomyopathy and sudden death resulting from constitutive activation of protein kinase a

CL Antos, N Frey, SO Marx, S Reiken… - Circulation …, 2001 - Am Heart Assoc
CL Antos, N Frey, SO Marx, S Reiken, M Gaburjakova, JA Richardson, AR Marks, EN Olson
Circulation research, 2001Am Heart Assoc
β-Adrenergic receptor (βAR) signaling, which elevates intracellular cAMP and enhances
cardiac contractility, is severely impaired in the failing heart. Protein kinase A (PKA) is
activated by cAMP, but the long-term physiological effect of PKA activation on cardiac
function is unclear. To investigate the consequences of chronic cardiac PKA activation in the
absence of upstream events associated with βAR signaling, we generated transgenic mice
that expressed the catalytic subunit of PKA in the heart. These mice developed dilated …
β-Adrenergic receptor (βAR) signaling, which elevates intracellular cAMP and enhances cardiac contractility, is severely impaired in the failing heart. Protein kinase A (PKA) is activated by cAMP, but the long-term physiological effect of PKA activation on cardiac function is unclear. To investigate the consequences of chronic cardiac PKA activation in the absence of upstream events associated with βAR signaling, we generated transgenic mice that expressed the catalytic subunit of PKA in the heart. These mice developed dilated cardiomyopathy with reduced cardiac contractility, arrhythmias, and susceptibility to sudden death. As seen in human heart failure, these abnormalities correlated with PKA-mediated hyperphosphorylation of the cardiac ryanodine receptor/Ca2+-release channel, which enhances Ca2+ release from the sarcoplasmic reticulum, and phospholamban, which regulates the sarcoplasmic reticulum Ca2+-ATPase. These findings demonstrate a specific role for PKA in the pathogenesis of heart failure, independent of more proximal events in βAR signaling, and support the notion that PKA activity is involved in the adverse effects of chronic βAR signaling.
Am Heart Assoc