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

被引:54
作者
Rogers, JH
Tsirka, A
Kovacs, A
Blumer, KJ
Dorn, GW
Muslin, AJ
机构
[1] Washington Univ, Sch Med, Cardiovasc Res Ctr, Dept Med, St Louis, MO 63110 USA
[2] Washington Univ, Sch Med, Dept Cell Biol & Physiol, St Louis, MO 63110 USA
[3] Washington Univ, Sch Med, Dept Pediat, St Louis, MO 63110 USA
[4] Univ Cincinnati, Coll Med, Dept Med, Cincinnati, OH 45267 USA
[5] Univ Cincinnati, Coll Med, Dept Pharmacol, Cincinnati, OH 45267 USA
基金
美国国家卫生研究院;
关键词
G protein; RGS; cardiac hypertrophy; signal transduction; transgenic mice;
D O I
10.1006/jmcc.2000.1307
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
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.
引用
收藏
页码:209 / 218
页数:10
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