Cardiac hypertrophy and heart failure development through Gq and CaM kinase II signaling.
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.
Department of Biomedical Sciences, University of California San Diego, La Jolla, CA, USA.
Shikha
S
Mishra
Haiyun
H
Ling
Michael
M
Grimm
Tong
T
Zhang
Don M
DM
Bers
Joan Heller
JH
Brown
D000818:Animals; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000502:physiology*; D006332:Cardiomegaly / Q000201:enzymology / Q000378:metabolism* / Q000503:physiopathology; D043802:GTP-Binding Protein alpha Subunits, Gq-G11 / Q000502:physiology*; D006333:Heart Failure / Q000201:enzymology / Q000378:metabolism* / Q000503:physiopathology; D006801:Humans; D015398:Signal Transduction / Q000502:physiology*
D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D043802:GTP-Binding Protein alpha Subunits, Gq-G11