Heart failure remains a leading cause of hospital admissions and mortality in the elderly and current interventional approaches often fail to treat the underlying cause of pathogenesis. Preservation of structure and function in the aging myocardium is most likely to be successful via ongoing cellular repair and replacement as well as enhanced survival of existing cardiomyocytes that generate contractile force. The long term goal of the study is to promote myocardial structure and function in the aging heart. The short term goal of this proposal is to enhance survival of cardiomyocytes and their precursor cells to render the heart resistant to effects of aging and pathological insults. The hypothesis of this proposal asserts that nuclear translocation of activated Akt promotes survival of cardiomyocytes and stem cell precursors to enhance myocardial viability and resist deterioration of cardiac structure and function from aging. Specifically, experiments are designed to understand the molecular and biological effects of targeting Akt kinase expression to the nucleus of cardiomyocytes and their progenitor cell population.
Specific aims of the proposal will demonstrate that: 1) Akt activity and nuclear translocation in cardiac stem cells are diminished with advancing age; 2) Nuclear-targeted Akt (Akt-nuc) activity increases cardiomyocyte proliferation, promotes survival, and antagonizes senescence in vitro; 3) Akt-nuc activity increases cardiomyocyte stem cell proliferation, promotes survival, and antagonizes senescence in vivo; and 4) myocardial-specific expression of Akt-nuc enhances hemodynamic function of the aging heart. Cardiomyocytes and their precursor cells will be characterized in genetically engineered transgenic mouse lines as well as recombinant viral vectors that express or activate Akt-nuc. Innovative combinations of in vitro and in vivo experiments are proposed utilizing molecular, biochemical, microscopic, and transgenic approaches to assess mechanisms that enhance stem cell survival and retard myocardial aging. The significance of these results will be to characterize a critical molecular regulatory pathway for cardiomyocyte progenitor survival that antagonizes cardiac senescence. Furthermore, significant implications exist for treatment of the aging myocardium as future interventional approaches will capitalize upon the use cardiac stem cells as therapeutic reagents.
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