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Dilated cardiomyopathy and sudden death resulting from constitutive activation of protein kinase a.
- Source :
-
Circulation research [Circ Res] 2001 Nov 23; Vol. 89 (11), pp. 997-1004. - Publication Year :
- 2001
-
Abstract
- beta-Adrenergic receptor (betaAR) 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 betaAR 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/Ca(2+)-release channel, which enhances Ca(2+) release from the sarcoplasmic reticulum, and phospholamban, which regulates the sarcoplasmic reticulum Ca(2+)-ATPase. These findings demonstrate a specific role for PKA in the pathogenesis of heart failure, independent of more proximal events in betaAR signaling, and support the notion that PKA activity is involved in the adverse effects of chronic betaAR signaling.
- Subjects :
- Animals
Calcium-Binding Proteins metabolism
Cardiomyopathy, Dilated enzymology
Cardiomyopathy, Dilated metabolism
Cyclic AMP-Dependent Protein Kinases genetics
Enzyme Activation
Humans
Mice
Mice, Transgenic
Myocardial Contraction
Myosin Heavy Chains genetics
Phosphorylation
Ryanodine Receptor Calcium Release Channel metabolism
Cardiomyopathy, Dilated etiology
Cyclic AMP-Dependent Protein Kinases metabolism
Cyclic AMP-Dependent Protein Kinases physiology
Death, Sudden, Cardiac etiology
Subjects
Details
- Language :
- English
- ISSN :
- 1524-4571
- Volume :
- 89
- Issue :
- 11
- Database :
- MEDLINE
- Journal :
- Circulation research
- Publication Type :
- Academic Journal
- Accession number :
- 11717156
- Full Text :
- https://doi.org/10.1161/hh2301.100003