TY - JOUR
T1 - Dilated cardiomyopathy and sudden death resulting from constitutive activation of protein kinase A
AU - Antos, Christopher L.
AU - Frey, Norbert
AU - Marx, Steven O.
AU - Reiken, Steven
AU - Gaburjakova, Marta
AU - Richardson, James A.
AU - Marks, Andrew R.
AU - Olson, Eric N.
N1 - Copyright:
Copyright 2017 Elsevier B.V., All rights reserved.
PY - 2001/11/23
Y1 - 2001/11/23
N2 - 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.
AB - 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.
KW - Dilated cardiomyopathy
KW - Protein kinase A
KW - Transgenic mice
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U2 - 10.1161/hh2301.100003
DO - 10.1161/hh2301.100003
M3 - Article
C2 - 11717156
AN - SCOPUS:0035941418
SN - 0009-7330
VL - 89
SP - 997
EP - 1004
JO - Circulation research
JF - Circulation research
IS - 11
ER -