REMODELING THE MAMMALIAN HEART USING TRANSGENESIS

Our objective was to test the hypothesis that, via transgenesis, one c an modify the contractile protein complement of the mouse heart. Using a promoter derived from the mouse myosin heavy chain gene (alpha-MyHC ), eve attempted to remodel the mouse myocardium by ectopically expres sing a ventricular form of the myosin light chain 2 (MLC2v) in the atr ium. The ability of the heart to maintain contractile isoform stoichio metry was tested by overexpressing the cDNA in both the atria and vent ricle. The promoter drove high levels of transgene expression in both cardiac compartments and was controlled in an appropriate manner durin g development. The data show that ectopic overexpression of a contract ile protein isoform can lead to compartment specific replacement. Howe ver, if the transgene encodes the isoform that is normally present (e. g., MLC2v expressed in the ventricle), the protein levels remain unaff ected, although the transgenic transcript accumulates to very high lev els. The basic function and the physiologic or pathophysiologic signif icance of differential MLC2 isoform content was examined. Using the wh ole working heart preparation, we show that an MLC2a-->MLC2v shift in the atrium severely affects contractile function and performance.