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Cardiac hypertrophy and heart failure development through Gq and CaM kinase II signaling.
- Source :
-
Journal of cardiovascular pharmacology [J Cardiovasc Pharmacol] 2010 Dec; Vol. 56 (6), pp. 598-603. - Publication Year :
- 2010
-
Abstract
- The molecular events associated with the development of pathological hypertrophy have been shown to be stimulated through G-protein–coupled receptors that activate Gq signaling pathways in neonatal cardiomyocytes and in transgenic (TG) and knockout mice. We demonstrated that CaMKII, a multifunctional Ca(2+)-regulated protein kinase, was activated through G-protein–coupled receptor and inositol trisphosphate–mediated Ca(2+) release and suggested that CaMKII was a downstream mediator of Gq-coupled hypertrophic signaling. This was supported by the demonstration of CaMKII activation by pressure overload [(transverse aortic constriction (TAC)] and induction of hypertrophy by TG CaMKII expression. CaMKII also phosphorylates Ca(2+) handling proteins including the ryanodine receptor (RyR2), phosphorylation of which markedly increases sarcoplasmic reticulum Ca(2+) leak. Increased RyR2 phosphorylation is associated with heart failure development in CaMKII TG mice, and mice genetically deleted for CaMKII (KO) have attenuated RyR2 phosphorylation, sarcoplasmic reticulum Ca(2+) leak, and heart failure development after long-term TAC. Genetic ablation of CaMKII also decreases development of heart failure in Gq TG mice and decreases infarct size, while improving functional recovery in mice subject to ischemia/reperfusion and preventing adverse remodeling after coronary artery occlusion. The underlying mechanisms are currently under study.
- Subjects :
- Animals
Cardiomegaly enzymology
Cardiomegaly physiopathology
Heart Failure enzymology
Heart Failure physiopathology
Humans
Calcium-Calmodulin-Dependent Protein Kinase Type 2 physiology
Cardiomegaly metabolism
GTP-Binding Protein alpha Subunits, Gq-G11 physiology
Heart Failure metabolism
Signal Transduction physiology
Subjects
Details
- Language :
- English
- ISSN :
- 1533-4023
- Volume :
- 56
- Issue :
- 6
- Database :
- MEDLINE
- Journal :
- Journal of cardiovascular pharmacology
- Publication Type :
- Academic Journal
- Accession number :
- 20531218
- Full Text :
- https://doi.org/10.1097/FJC.0b013e3181e1d263