title: G-protein signaling participates in the development of diabetic cardiomyopathy.
abstract: Diabetic patients develop a cardiomyopathy that consists of ventricular hypertrophy and diastolic dysfunction. Although the pathogenesis of this condition is poorly understood, previous studies implicated abnormal G-protein activation. In this work, mice with cardiac overexpression of the transcription factor peroxisome proliferator-activated receptor-alpha (PPAR-alpha) were examined as a model of diabetic cardiomyopathy. PPAR-alpha transgenic mice develop spontaneous cardiac hypertrophy, contractile dysfunction, and "fetal" gene induction. We examined the role of abnormal G-protein activation in the pathogenesis of cardiac dysfunction by crossing PPAR-alpha mice with transgenic mice with cardiac-specific overexpression of regulator of G-protein signaling subtype 4 (RGS4), a GTPase activating protein for Gq and Gi. Generation of compound transgenic mice demonstrated that cardiac RGS4 overexpression ameliorated the cardiomyopathic phenotype that occurred as a result of PPAR-alpha overexpression without affecting the metabolic abnormalities seen in these hearts. Next, transgenic mice with increased or decreased cardiac Gq signaling were made diabetic by injection with streptozotocin (STZ). RGS4 transgenic mice were resistant to STZ-induced cardiac fetal gene induction. Transgenic mice with cardiac-specific expression of mutant Galphaq, Galphaq-G188S, that is resistant to RGS protein action were sensitized to the development of STZ-induced cardiac fetal gene induction and bradycardia. These results establish that Gq-mediated signaling plays a critical role in the pathogenesis of diabetic cardiomyopathy.
authors.affiliation: Center for Cardiovascular Research, Department of Internal Medicine, Washington University School of Medicine, St. Louis, Missouri, USA.
authors.forename: Ian S
authors.initials: IS
authors.lastname: Harris
authors.forename: Ilya
authors.initials: I
authors.lastname: Treskov
authors.forename: Michael W
authors.initials: MW
authors.lastname: Rowley
authors.forename: Scott
authors.initials: S
authors.lastname: Heximer
authors.forename: Kevin
authors.initials: K
authors.lastname: Kaltenbronn
authors.forename: Brian N
authors.initials: BN
authors.lastname: Finck
authors.forename: Richard W
authors.initials: RW
authors.lastname: Gross
authors.forename: Daniel P
authors.initials: DP
authors.lastname: Kelly
authors.forename: Kendall J
authors.initials: KJ
authors.lastname: Blumer
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Muslin
mesh_terms: D000818:Animals; D009202:Cardiomyopathies / Q000235:genetics* / Q000503:physiopathology; D003921:Diabetes Mellitus, Experimental / Q000235:genetics* / Q000503:physiopathology; D003925:Diabetic Angiopathies / Q000235:genetics* / Q000503:physiopathology; D019204:GTP-Binding Proteins / Q000235:genetics / Q000502:physiology*; D008285:Major Histocompatibility Complex; D051379:Mice; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D008822:Mice, Transgenic; D047493:PPAR alpha / Q000235:genetics / Q000502:physiology*; D017354:Point Mutation; D020710:RGS Proteins / Q000235:genetics* / Q000502:physiology
chemical_list: D047493:PPAR alpha; D020710:RGS Proteins; C491349:RGS5 protein, human; C098799:RGS4 protein; D019204:GTP-Binding Proteins