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

Jason H. Rogers, Anna Tsirka, Attila Kovacs, Kendall J. Blumer, Gerald W. Dorn, Anthony J. Muslin

Research output: Contribution to journalArticle

55 Scopus citations

Abstract

The intrinsic GTPase activity of Gαq 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 Gαq 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 Gαq and Gαi 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 Gαq-specific GTPase activating protein (GAP) in the in vivo heart, dual transgenic Gαq-40xRGS4 mice were generated to determine if RGS4 co-expression would ameliorate the Gαq-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 Gαq in the in vivo heart, and demonstrate that its regulated expression can have pathophysiologic consequences.

Original languageEnglish
Pages (from-to)209-218
Number of pages10
JournalJournal of Molecular and Cellular Cardiology
Volume33
Issue number2
DOIs
StatePublished - Jan 1 2001

Keywords

  • Cardiac hypertrophy
  • G protein
  • RGS
  • Signal transduction
  • Transgenic mice

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