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

The intrinsic GTPase activity of G_αq 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_αq in myocardium exhibit cardiac hypertrophy, enhanced PKCε membrane translocation, embryonic gene expression, and depressed cardiac contractility. We recently reported that transgenic mice with cardiac-specific expression of RGS4, a G_αq and G_αi 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_αq-specific GTPase activating protein (GAP) in the in vivo heart, dual transgenic G_αq-40xRGS4 mice were generated to determine if RGS4 co-expression would ameliorate the G_αq-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. PKCε membrane translocation and ANF and α-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_αq in the in vivo heart, and demonstrate that its regulated expression can have pathophysiologic consequences.