title: RGS4 causes increased mortality and reduced cardiac hypertrophy in response to pressure overload.
abstract: RGS family members are GTPase-activating proteins (GAPs) for heterotrimeric G proteins. There is evidence that altered RGS gene expression may contribute to the pathogenesis of cardiac hypertrophy and failure. We investigated the ability of RGS4 to modulate cardiac physiology using a transgenic mouse model. Overexpression of RGS4 in postnatal ventricular tissue did not affect cardiac morphology or basal cardiac function, but markedly compromised the ability of the heart to adapt to transverse aortic constriction (TAC). In contrast to wild-type mice, the transgenic animals developed significantly reduced ventricular hypertrophy in response to pressure overload and also did not exhibit induction of the cardiac "fetal" gene program. TAC of the transgenic mice caused a rapid decompensation in most animals characterized by left ventricular dilatation, depressed systolic function, and increased postoperative mortality when compared with nontransgenic littermates. These results implicate RGS proteins as a crucial component of the signaling pathway involved in both the cardiac response to acute ventricular pressure overload and the cardiac hypertrophic program.
authors.affiliation: Center for Cardiovascular Research, Department of Medicine, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
authors.forename: J H
authors.initials: JH
authors.lastname: Rogers
authors.forename: P
authors.initials: P
authors.lastname: Tamirisa
authors.forename: A
authors.initials: A
authors.lastname: Kovacs
authors.forename: C
authors.initials: C
authors.lastname: Weinheimer
authors.forename: M
authors.initials: M
authors.lastname: Courtois
authors.forename: K J
authors.initials: KJ
authors.lastname: Blumer
authors.forename: D P
authors.initials: DP
authors.lastname: Kelly
authors.forename: A J
authors.initials: AJ
authors.lastname: Muslin
mesh_terms: D000222:Adaptation, Physiological / Q000235:genetics; D000316:Adrenergic alpha-Agonists / Q000494:pharmacology; D000818:Animals; D001013:Aorta, Thoracic; D017209:Apoptosis; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism; D003250:Constriction; D020690:GTPase-Activating Proteins; D005786:Gene Expression Regulation; D006339:Heart Rate; D017379:Hypertrophy, Left Ventricular / Q000209:etiology* / Q000235:genetics / Q000503:physiopathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009200:Myocardial Contraction / Q000187:drug effects; D009206:Myocardium / Q000473:pathology; D018995:Myosin Heavy Chains / Q000235:genetics; D010656:Phenylephrine / Q000494:pharmacology; D011312:Pressure; D011401:Promoter Regions, Genetic; D011506:Proteins / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction; D018487:Ventricular Dysfunction, Left / Q000209:etiology* / Q000235:genetics / Q000503:physiopathology
chemical_list: D000316:Adrenergic alpha-Agonists; D020690:GTPase-Activating Proteins; D011506:Proteins; D010656:Phenylephrine; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D018995:Myosin Heavy Chains