RGS4 reduces contractile dysfunction and hypertrophic gene induction in Gαq overexpressing mice

The intrinsic GTPase activity of G(alphaq) is low, and RGS proteins which activate GTPase are expressed in the heart; however, their functional relevance in vivo is unknown. Transgenic mice with cardiac-specific overexpression of G(alphaq) in myocardium exhibit cardiac hypertrophy, enhanced PI(CE membrane translocation, embryonic gene expression, and depressed cardiac contractility. We recently reported that transgenic mice with cardiac-specific expression of RGS4, a G(alphaq) and G(alphai) GTPase activator, exhibit decreased left ventricular hypertrophy and ANF induction in response to pressure overload. To test the hypothesis that RGS4 can act as a G(alphaq)-specific GTPase activating protein (GAP) in the in vivo heart, dual transgenic G(alphaq)-40xRGS4 mice were generated to determine if RGS4 co-expression would ameliorate the G(alphaq)-40 phenotype. At age 4 weeks, percent fractional shortening was normalized in dual transgenic mice as was left ventricular internal dimension and posterior and septal wall thicknesses. PKC epsilon membrane translocation and ANF and alpha -skeletal actin mRNA levels were also normalized. Compound transgenic mice eventually developed depressed cardiac contractility that was evident by 9 weeks of age. These studies establish for the first time a role for RGS4 as a GAP for G(alphaq) in the in vivo heart, and demonstrate that its regulated expression can have pathophysiologic consequences. (C) 2001 Academic Press.