title: Determinants of the cardiomyopathic phenotype in chimeric mice overexpressing cardiac Gsalpha.
abstract: Mice with overexpressed cardiac Gsalpha develop cardiomyopathy, characterized by myocyte hypertrophy and extensive myocardial fibrosis. The cardiomyopathy likely involves chronically enhanced beta-adrenergic signaling, because it can be blocked with long-term propranolol treatment. It remains unknown whether the genotype of the myocyte is solely responsible for the progressive pathological changes. A chimeric population in the heart should answer this question. Accordingly, we developed a chimeric animal, which combined cells from a transgenic overexpressed Gsalpha parent and a Rosa mouse containing the LacZ reporter gene, facilitating identification of the non-Gsalpha cells, which express a blue color with exposure to beta-galactosidase. We studied these animals at 14 to 17 months of age (when cardiomyopathy should have been present), with the proportion of Gsalpha cells in the myocardium ranging from 5% to 88%. beta-Galactosidase staining of the hearts demonstrated Gsalpha and Rosa cells, exhibiting a mosaic pattern. The fibrosis and hypertrophy, characteristic of the cardiomyopathy, were not distributed randomly. There was a direct correlation (r=0.85) between the extent of myocyte hypertrophy (determined by computer imaging) and the quantity of Gsalpha cells. The fibrosis, determined by picric acid Sirius red, was also more prominent in areas with the greatest Gsalpha cell density, with a correlation of r=0.88. Thus, the overexpressed Gsalpha can exert its action over the life of the animal, resulting in a local picture of cardiomyopathic damage in discrete regions of the heart, where clusters of the overexpressed Gsalpha cells reside, sparing the clusters of normal cells derived from the normal Rosa parent.
authors.affiliation: Weis Center for Research, Pennsylvania State University College of Medicine, Danville, PA 17822-2601, USA.
authors.forename: D E
authors.initials: DE
authors.lastname: Vatner
authors.forename: G P
authors.initials: GP
authors.lastname: Yang
authors.forename: Y J
authors.initials: YJ
authors.lastname: Geng
authors.forename: K
authors.initials: K
authors.lastname: Asai
authors.forename: J S
authors.initials: JS
authors.lastname: Yun
authors.forename: T E
authors.initials: TE
authors.lastname: Wagner
authors.forename: Y
authors.initials: Y
authors.lastname: Ishikawa
authors.forename: S P
authors.initials: SP
authors.lastname: Bishop
authors.forename: C J
authors.initials: CJ
authors.lastname: Homcy
authors.forename: S F
authors.initials: SF
authors.lastname: Vatner
mesh_terms: D000818:Animals; D001794:Blood Pressure; D009202:Cardiomyopathies / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D002678:Chimera; D004452:Echocardiography; D019205:GTP-Binding Protein alpha Subunits, Gs / Q000235:genetics / Q000502:physiology*; D006321:Heart / Q000503:physiopathology*; D006339:Heart Rate; D006439:Hemodynamics; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009028:Morula; D009206:Myocardium / Q000473:pathology; D010641:Phenotype; D011401:Promoter Regions, Genetic; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis; D001616:beta-Galactosidase / Q000235:genetics
chemical_list: D011993:Recombinant Fusion Proteins; D001616:beta-Galactosidase; D019205:GTP-Binding Protein alpha Subunits, Gs