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

beta -Adrenergic receptor (beta AR) signaling, which elevates intracellular cAMP and enhances cardiac contractility, is severely impaired in the faili ng heart. Protein kinase A (PKA) is activated by cAMP, but the long-term ph ysiological effect of PKA activation on cardiac function is unclear. To inv estigate the consequences of chronic cardiac PKA activation in the absence of upstream events associated with beta AR signaling, we generated transgen ic mice, that expressed the catalytic subunit of PKA in the heart. These mi ce developed dilated cardiomyopathy with reduced cardiac contractility, arr hythmias, and susceptibility to sudden death. As seen in human heart failur e, these abnormalities correlated with PKA-mediated hyperphosphorylation of the cardiac ryanodine receptor/Ca2+-release channel, which enhances Ca2+ r elease from the sarcoplasmic reticulum, and phospholamban, which regulates the sarcoplasmic reticulum Ca2+-ATPase. These findings demonstrate a specif ic role for PKA in the pathogenesis of heart failure, independent of more p roximal events in beta AR signaling, and support the notion that PKA activi ty is involved in the adverse effects of chronic beta AR signaling.