Regular Article
RGS4 Reduces Contractile Dysfunction and Hypertrophic Gene Induction in Gα qOverexpressing Mice

https://doi.org/10.1006/jmcc.2000.1307Get rights and content

Abstract

The intrinsic GTPase activity of Gα qis 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 Gα qin myocardium exhibit cardiac hypertrophy, enhanced PKCξ membrane translocation, embryonic gene expression, and depressed cardiac contractility. We recently reported that transgenic mice with cardiac-specific expression of RGS4, a Gα qand Gα iGTPase activator, exhibit decreased left ventricular hypertrophy and ANF induction in response to pressure overload. To test the hypothesis that RGS4 can act as a Gα q-specific GTPase activating protein (GAP) in the in vivo heart, dual transgenic Gα q-40xRGS4 mice were generated to determine if RGS4 co-expression would ameliorate the Gα q-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 ξ 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 Gα qin the in vivo heart, and demonstrate that its regulated expression can have pathophysiologic consequences.

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    Please address all correspondence to: Anthony J. Muslin, Center for Cardiovascular Research, Box 8086, Washington University School of Medicine, 660 S. Euclid Avenue, St. Louis, MO 63110, USA. Tel: +1 314 747 3525; Fax: +1 314 362 0186; E-mail: [email protected]

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