title: SRC-2 coactivator deficiency decreases functional reserve in response to pressure overload of mouse heart.
abstract: A major component of the cardiac stress response is the simultaneous activation of several gene regulatory networks. Interestingly, the transcriptional regulator steroid receptor coactivator-2, SRC-2 is often decreased during cardiac failure in humans. We postulated that SRC-2 suppression plays a mechanistic role in the stress response and that SRC-2 activity is an important regulator of the adult heart gene expression profile. Genome-wide microarray analysis, confirmed with targeted gene expression analyses revealed that genetic ablation of SRC-2 activates the "fetal gene program" in adult mice as manifested by shifts in expression of a) metabolic and b) sarcomeric genes, as well as associated modulating transcription factors. While these gene expression changes were not accompanied by changes in left ventricular weight or cardiac function, imposition of transverse aortic constriction (TAC) predisposed SRC-2 knockout (KO) mice to stress-induced cardiac dysfunction. In addition, SRC-2 KO mice lacked the normal ventricular hypertrophic response as indicated through heart weight, left ventricular wall thickness, and blunted molecular signaling known to activate hypertrophy. Our results indicate that SRC-2 is involved in maintenance of the steady-state adult heart transcriptional profile, with its ablation inducing transcriptional changes that mimic a stressed heart. These results further suggest that SRC-2 deletion interferes with the timing and integration needed to respond efficiently to stress through disruption of metabolic and sarcomeric gene expression and hypertrophic signaling, the three key stress responsive pathways.
authors.affiliation: Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas, United States of America.
authors.forename: Erin L
authors.initials: EL
authors.lastname: Reineke
authors.forename: Brian
authors.initials: B
authors.lastname: York
authors.forename: Erin
authors.initials: E
authors.lastname: Stashi
authors.forename: Xian
authors.initials: X
authors.lastname: Chen
authors.forename: Anna
authors.initials: A
authors.lastname: Tsimelzon
authors.forename: Jianming
authors.initials: J
authors.lastname: Xu
authors.forename: Christopher B
authors.initials: CB
authors.lastname: Newgard
authors.forename: George E
authors.initials: GE
authors.lastname: Taffet
authors.forename: Heinrich
authors.initials: H
authors.lastname: Taegtmeyer
authors.forename: Mark L
authors.initials: ML
authors.lastname: Entman
authors.forename: Bert W
authors.initials: BW
authors.lastname: O'Malley
mesh_terms: D000818:Animals; D006352:Heart Ventricles / Q000378:metabolism / Q000503:physiopathology; D017379:Hypertrophy, Left Ventricular / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D051379:Mice; D018345:Mice, Knockout; D009206:Myocardium / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000378:metabolism; D051958:Nuclear Receptor Coactivator 2 / Q000235:genetics* / Q000378:metabolism; D018487:Ventricular Dysfunction, Left / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D020257:Ventricular Remodeling / Q000235:genetics
chemical_list: D051958:Nuclear Receptor Coactivator 2