Determinants of the cardiomyopathic phenotype in chimeric mice overexpressing cardiac Gs alpha

Mice with overexpressed cardiac Gsa develop cardiomyopathy, characterized b y 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 wh ether the genotype of the myocyte is solely responsible for the progressive pathological changes. A chimeric population in the heart should answer thi s question. Accordingly, we developed a chimeric animal, which combined cel ls from a transgenic overexpressed Gs alpha parent and a Rosa mouse contain ing the LacZ reporter gene, facilitating identification of the non-Gs alpha 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 Gsa cells in the myocardium ran ging from 5% to 88%. beta-Galactosidase staining of the hearts demonstrated Gs alpha and Rosa cells, exhibiting a mosaic pattern. The fibrosis and hyp ertrophy, characteristic of the cardiomyopathy, were not distributed random ly. There was a direct correlation (r=0.85) between the extent of myocyte h ypertrophy (determined by computer imaging) and the quantity of Gs alpha ce lls. The fibrosis, determined by picric acid Sirius red, was also more prom inent in areas with the greatest Gs alpha cell density, with a correlation of r=0.88. Thus, the overexpressed Gs alpha can exert its action over the l ife of the animal, resulting in a local picture of cardiomyopathic damage i n discrete regions of the heart, where clusters of the overexpressed Gs alp ha cells reside, sparing the clusters of normal cells derived from the norm al Rosa parent.