Cardiac hypertrophy and heart failure development through Gq and CaM kinase II signaling

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.

Figure 1

Activation and targets of CaMKII δ in hypertrophy and heart failure. Abbreviations: ET-1, Endothelin-1; Phe, Phenylephrine; GPCR, G-Protein Coupled Receptor; α, α subunit of the Gq-protein; β◻, β◻ subunit of the Gq-protein; PIP₂, Phosphatidylinositol 4,5-Bisphosphate; PLC, Phospholipase C; DAG, Diacylglycerol; PKC, Protein Kinase C; PKD, Protein Kinase D; CaM, Calmodulin; PLN, Phospholamban; SR, Sarcoplasmic Reticulum; SERCA, SR Ca²⁺ ATPase; CaMKII δ, Calcium Calmodulin Dependent Protein Kinase II; RyR2, Ryanodine Receptor 2; IP₃, Inositol (1,4,5)-Trisphosphate; HDAC, Histone Deacetylase; IP₃R, IP₃ Receptor; Mito; Mitochondria; PTP, Permeability Transition Pore; MEF2, Myocyte Enhancer Factor-2.