TRANSGENIC REMODELING OF THE CONTRACTILE APPARATUS IN THE MAMMALIAN HEART

The structure-function relationships of the sarcomeric proteins in the mammalian cardiac compartment remain ill-defined because of the lack of a suitable model in which they can be readily manipulated or exchan ged in vivo. To establish the validity of the transgenic paradigm for remodeling the mammalian heart, the murine alpha-cardiac myosin heavy chain gene promoter was used to express a ventricular myosin light cha in-2 transgene (MLC2v) in both the atria and ventricles of the adult a nimal. Expression resulted in high levels of the transgene's transcrip t in both compartments. In the ventricle, the transgene was expressed against the background expression of the normal isoform. In the atrium , the transgene's expression would be ectopic, in that normally, MLC2v expression is restricted to the ventricle. Ectopic expression of the transgene in the atria resulted in a complete replacement of the atria l myosin light chain-2 protein isoform, although the endogenous isofor m's steady state transcript levels were unchanged. In contrast, ventri cular expression of the transgene had no effect at the protein level, despite an eightfold increase in MLC2v transcript levels. The data sho w that sarcomeric protein stoichiometry is maintained rigorously via p osttranscriptional regulation and that protein replacement can be achi eved through a single transgenic manipulation.