Decompensation of Pressure-Overload Hypertrophy in Gαq-Overexpressing Mice

Abstract

Background —Receptor-mediated activation of myocardial Gq signaling is postulated as a biochemical mechanism transducing pressure-overload hypertrophy. The specific effects of Gq activation on the functional and morphological adaptations to pressure overload are not known. Methods and Results —To determine the effects of intrinsic myocyte Gαq signaling on the left ventricular hypertrophic response to experimental pressure overload, transgenic mice overexpressing Gαq specifically in the heart (Gαq-25) and nontransgenic siblings underwent microsurgical creation of transverse aortic coarctation and the morphometric, functional, and molecular characteristics of these pressure-overloaded hearts were compared at increasing times after surgery. Before aortic banding, isolated Gαq-25 ventricular myocytes exhibited contractile depression (depressed +dl/dt and −dl/dt) and Gαq-25 hearts showed a pattern of fetal gene expression similar to the known characteristics of nontransgenic pressure-overloaded mice. Three weeks after transverse aortic banding, Gαq-25 left ventricles hypertrophied to a similar extent (≈30% increase) as nontransgenic mice. However, whereas nontransgenic mice exhibited concentric left ventricular remodeling with maintained ejection performance (compensated hypertrophy), Gαq-25 left ventricles developed eccentric hypertrophy and ejection performance deteriorated, ultimately resulting in left heart failure (decompensated hypertrophy). The signature hypertrophy-associated progress of fetal cardiac gene expression observed at baseline in Gαq-25 developed after aortic banding of nontransgenic mice but did not significantly change in aortic-banded Gαq-25 mice. Conclusions —Intrinsic cardiac myocyte Gαq activation stimulates fetal gene expression and depresses cardiac myocyte contractility. Superimposition of the hemodynamic stress of pressure overload on Gαq overexpression stimulates a maladaptive form of eccentric hypertrophy that leads to rapid functional decompensation. Therefore Gαq-stimulated cardiac hypertrophy is functionally deleterious and compromises the ability of the heart to adapt to increased mechanical load. This finding supports a reevaluation of accepted concepts regarding the mechanisms for compensation and decompensation in pressure-overload hypertrophy.