REGULATION OF CARDIOMYOCYTE GROWTH

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Increases in cardiac mass during normal development are characterized by proliferation of differentiated cardiomyocytes. After birth there is a dramatic reduction in the rate of cardiomyocyte cell cycle activity, and subsequent increases in cardiac mass occur largely as a consequence of cardiomyocyte hypertrophy. Abnormalities in these developmental processes can give rise to congenital heart defects. Moreover, the absence of substantive postnatal cardiomyocyte cell cycle activity, coupled with cardiomyocyte loss (via apoptosis and/or other mechanisms), contributes significantly to morbidity and mortality in neonatal patients with congestive heart failure. We have generated a number of mouse models which exhibit enhanced cardiomyocyte cell cycle activity during embryonic and postnatal life. We have also generated mouse models that exhibit reduced hypertrophic growth during neonatal life and which are resistant to injury- induced cardiomyocyte apoptosis as a consequence of targeted BmpIO expression. The proposed experiments will use these models to explore the regulation of cardiomyocyte apoptosis and hyperplastic cardiomyocyte growth in the setting of neonatal heart failure. Specific Aim 1a will test the hypothesis that BmpIO expression can exert cardioprotective activity in response to acquired injuries which model childhood heart failure in humans (namely anthracycline cardiotoxicity and viral myocarditis). Specific Aim 1b will test the hypothesis that BmpIO functions via paracrine pathways in the postnatal heart, and will also determine how long ventricular cardiomyocytes remain responsive to cytokine-mediated cardioprotection. Specific Aim 2a will test the hypothesis that inhibition of hypertrophic growth renders postnatal cardiomyocytes more susceptible to cell cycle re-entry. Specific Aim 2b will test the hypothesis that induction of cardiomyocyte cell cycle activity can reverse the adverse consequences of congenital and acquired injuries which give rise to childhood heart failure. The proposed studies will benefit greatly from the organization of the Program Grant application, in that many reagents, techniques and mouse models developed in the other projects will be used here. The ultimate goal of this project is to gain an understanding of how regulation of cardiomyocyte apoptosis and hyperplastic cardiomyocyte growth can be exploited to protect at-risk myocardium, and/or to promote the formation of new heart tissue, in the setting of childhood heart failure.