The present proposal addresses four questions: 1. Is myocyte cell death an early phenomenon of the aging heart which becomes more severe in the old myocardium? 2. Is myocyte cell death with aging not only necrotic in nature but also mediated by activation of the suicide program of the cells? 3. Is the increase in programmed cell death with aging coupled with stimulation of myocyte hypertrophy and hyperplasia, and the induction of genes modulating myocyte cell death? and 4 . Does hypertension potentiate programmed cell death in the aging heart by stimulating effector pathways which regulate hypertrophic and hyperplastic myocyte growth? The premise of this research is that programmed cell death is considered to be an intrinsic aspect of the aging myocardium and that activation of early growth related genes, such as c-myc, during aging induced myocyte hypertrophy, may trigger the suicide program of the cells. Similarly, the surface molecule Fas may become overexpressed in enlarging myocytes exposed to excessive mechanical loading and this may initiate programmed cell death. The possibility also is advanced that the antioncogene p53 may be coupled with the stimulation of apoptosis in myocytes undergoing DNA synthesis and proliferation. Myocytes with DNA damage may be required by p53 to repair DNA or activate the suicide program. Since the protooncogene bcl-2 protects from apoptosis, the assumption is made that growth processes in myocytes are associated with low levels of expression of bcl-2 in the cells, facilitating myocyte cell death. Hypertension superimposed on aging is postulated to enhance programmed cell death not only because physical forces on the myocardium may activate apoptosis but also because this hemodynamic condition leads to myocyte hypertrophy and proliferation. Finally, since activation of the local renin-angiotensin system in the myocardium has been linked to the incitation of myocyte hypertrophy, and stimulation of the IGF-1 autocrine system to DNA synthesis and myocyte proliferation, the hypothesis has been developed that upregulation of these effector pathways may be coupled with the induction of programmed cell death in the hypertensive aging heart. Thus, the imbalance between myocyte growth and myocyte cell death may be the determining factor in precipitating cardiac failure in the overloaded heart of elderly patients.
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