""""""""Irreversible"""""""" cell cycle exit limits the restoration of pump function after myocardial infarction or cell death in heart failure. Hence, mechanisms underlying cardiac cell cycle exit are of particular importance, given the therapeutic potential of regenerative cardiac myocyte growth. Efforts to promote or sustain cardiac myocyte proliferation include both loss- and gain-of-function mutations in mice. However, the apparent necessity for multiple cell cycle regulators acting in concert creates a substantial barrier to ventricular myocyte proliferation beyond the immediate perinatal period. For species with linear chromosomes, telomere shortening now is recognized as a pivotal component of replicative senescence. Given that telomerase activity and telomerase reverse transcriptase (TERT) expression both are minimal or lacking in the adult heart, we postulated that preventing the down-regulation of TERT might delay or prevent the loss of telomerase activity and, if so, delay or prevent ventricular myocytes' exit from the cell cycle. To test this hypothesis, exogenous TERT was forcibly expressed in the myocardium of transgenic mice. TERT overexpression, by itself, was sufficient to restore telomerase activity in the adult heart and delayed ventricular myocytes' exit from the cell cycle, for at least one month after birth. Less expectedly, cardiac myocyte hypertrophy was evident at 12 weeks of age, without evidence of mechanical dysfunction or fibrosis as initiating factors. Cardiac hyperplasia was associated with up-regulation of endogenous Cdk activities, whereas hypertrophy was not. Conversely, cardiac hypertrophy was associated with activation of endogenous p70 S6 kinase (S6K). Using viral gene transfer, hypertrophy including p70 S6K activation also was elicited, acutely, in cultured cardiac myocytes by catalytically active TERT (but not inactive TERT), suggesting additional functions of the protein beyond those reported to date. Based on these initial results, the Specific Aims of this competing renewal are: (1) To characterize the hyperplastic cardiac phenotype induced by TERT, with emphasis on the catalytic activity of TERT and tests for synergy with the pocket protein/Cdk pathway controlling cardiac growth arrest. (2) To characterize the hypertrophic cardiac phenotype induced by TERT, with emphasis on potential mediators including p70 S6K, and its activation by ATM/PIK family kinases that couple altered DNA structure to signal transduction cascades.
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