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(Circulation Research. 2000;86:802.)
© 2000 American Heart Association, Inc.

Integrative Physiology

Determinants of the Cardiomyopathic Phenotype in Chimeric Mice Overexpressing Cardiac Gs

Dorothy E. Vatner¹, Gui-Ping Yang¹, Yong-Jian Geng, Kuniya Asai, Jeung S. Yun, Thomas E. Wagner, Yoshihiro Ishikawa, Sanford P. Bishop, Charles J. Homcy, Stephen F. Vatner

From the Weis Center for Research (D.E.V., G.-P.Y., Y.-J.G., K.A., Y.I., S.P.B., S.F.V.), Pennsylvania State University College of Medicine, Danville, Pa, and Allegheny University of the Health Sciences, Pittsburgh, Pa; Oncology Research Institute (J.S.Y., T.E.W.), Greenville Hospital System and Clemson University, Greenville, SC; and COR Therapeutics, Inc (C.J.H.), South San Francisco, Calif.

Correspondence to Stephen F. Vatner, MD, Director of the Henry Hood Research Program, Charles B. Degenstein Professor, Weis Center for Research, Pennsylvania State University College of Medicine, 100 N Academy Ave, Danville, PA 17822-2601. E-mail svatner{at}psghs.edu

Abstract—Mice with overexpressed cardiac Gs develop cardiomyopathy, characterized by myocyte hypertrophy and extensive myocardial fibrosis. The cardiomyopathy likely involves chronically enhanced ß-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 Gs parent and a Rosa mouse containing the LacZ reporter gene, facilitating identification of the non–Gs cells, which express a blue color with exposure to ß-galactosidase. We studied these animals at 14 to 17 months of age (when cardiomyopathy should have been present), with the proportion of Gs cells in the myocardium ranging from 5% to 88%. ß-Galactosidase staining of the hearts demonstrated Gs 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 Gs cells. The fibrosis, determined by picric acid Sirius red, was also more prominent in areas with the greatest Gs cell density, with a correlation of r=0.88. Thus, the overexpressed Gs 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 Gs cells reside, sparing the clusters of normal cells derived from the normal Rosa parent.

Key Words: hypertrophy • cardiomyopathy • heart failure • ß-adrenergic receptor • sympathetic nervous system

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