title: RGS4 reduces contractile dysfunction and hypertrophic gene induction in Galpha q overexpressing mice.
abstract: The intrinsic GTPase activity of Galpha q 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 Galpha q in myocardium exhibit cardiac hypertrophy, enhanced PKC xi membrane translocation, embryonic gene expression, and depressed cardiac contractility. We recently reported that transgenic mice with cardiac-specific expression of RGS4, a Galpha q and Galpha i 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 Galpha q-specific GTPase activating protein (GAP) in the in vivo heart, dual transgenic Galpha q-40xRGS4 mice were generated to determine if RGS4 co-expression would ameliorate the Galpha 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 xi 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 Galpha q in the in vivo heart, and demonstrate that its regulated expression can have pathophysiologic consequences.
authors.affiliation: Center for Cardiovascular Research, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: J H
authors.initials: JH
authors.lastname: Rogers
authors.forename: A
authors.initials: A
authors.lastname: Tsirka
authors.forename: A
authors.initials: A
authors.lastname: Kovacs
authors.forename: K J
authors.initials: KJ
authors.lastname: Blumer
authors.forename: G W
authors.initials: GW
authors.lastname: Dorn
authors.forename: A J
authors.initials: AJ
authors.lastname: Muslin
mesh_terms: D000199:Actins / Q000378:metabolism; D000818:Animals; D009320:Atrial Natriuretic Factor / Q000378:metabolism; D015152:Blotting, Northern; D015153:Blotting, Western; D006332:Cardiomegaly / Q000235:genetics*; D002467:Cell Nucleus / Q000378:metabolism; D004452:Echocardiography; D020690:GTPase-Activating Proteins / Q000378:metabolism; D007527:Isoenzymes / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D018482:Muscle, Skeletal / Q000378:metabolism; D009200:Myocardial Contraction / Q000502:physiology*; D010641:Phenotype; D011493:Protein Kinase C / Q000378:metabolism; D051744:Protein Kinase C-epsilon; D021381:Protein Transport; D020710:RGS Proteins / Q000378:metabolism* / Q000502:physiology*; D012333:RNA, Messenger / Q000378:metabolism; D013997:Time Factors
chemical_list: D000199:Actins; D020690:GTPase-Activating Proteins; D007527:Isoenzymes; D020710:RGS Proteins; D012333:RNA, Messenger; C098799:RGS4 protein; D009320:Atrial Natriuretic Factor; C497256:Prkce protein, mouse; D011493:Protein Kinase C; D051744:Protein Kinase C-epsilon