RGS4 causes increased mortality and reduced cardiac hypertrophy in response to pressure overload

RGS family members are GTPase-activating proteins (GAPs) for heterotrimeric G proteins. There is evidence that altered RGS gene expression may contrib ute to the pathogenesis of cardiac hypertrophy and failure. We investigated the ability of RGS4 to modulate cardiac physiology using a transgenic mous e model. Overexpression of RGS4 in postnatal ventricular tissue did not aff ect cardiac morphology or basal cardiac function, but markedly compromised the ability of the heart to adapt to transverse aortic constriction (TAC). In contrast to wild-type mice, the transgenic animals developed significant ly reduced ventricular hypertrophy in response to pressure overload and als o did not exhibit induction of the cardiac "fetal" gene program. TAC of the transgenic mice caused a rapid decompensation in most animals characterize d by left ventricular dilatation, depressed systolic function, and increase d postoperative mortality when compared with nontransgenic littermates. The se results implicate RGS proteins as a crucial component of the signaling p athway involved in both the cardiac response to acute ventricular pressure overload and the cardiac hypertrophic program.