The long-term objective of this application is to measure quantitatively myocyte necrosis, apoptosis and apoptosis-necrosis in a large number of hearts obtained from patients undergoing cardiac transplantation or who died from end-stage heart failure. This information, collected separately in women and men, will be correlated with clinical data to establish whether gender differences and age play important roles in the magnitude of ongoing cell death and the terminal evolution of the cardiac disease. An identical analysis will be conducted in normal female and male human hearts as a function of age to identify whether sex influences the extent of cell death and regeneration in the myocardium throughout life. The central hypothesis is that women possess an enhanced cellular IGF-1-IGF-1R system which protects myocytes from multiple death signals and potentiates cell division. This greater defense mechanism and ability to regenerate of female myocytes may be responsible for the lower incidence of heart failure with overload and aging, and longer life span of women in the industrialized world. Importantly, if myocytes proliferate, the age of an individual will not correspond to the age of myocytes since this cell population may consist of young, adult, old and senescent cells. The proportion of these cell categories may vary between women and men. If IGF- 1 is critical for the reentry of myocytes into the cell cycle, loss of surface IGF-1R may characterize the early phases of cellular aging, whereas the accumulation of p16, lipofuscin and p130-E2F4 complexes may be employed as indicators of distinct phases of this phenomenon. Lack of IGF-1R, DNA damage and accumulation of p16 and lipofuscin may characterize the senescent phenotype and the susceptibility of myocytes to die. Colocalization of p130 and E2F4 may identify younger myocytes which are still capable of replicating in the old heart. The analysis of these possibilities in a causative manner would require molecular manipulation of the IGF-1 system in human myocytes, which is currently impossible. Therefore, myocyte size and number, ongoing cell death and division, distribution of surface IGF-1R, presence of multiple markers of cellular aging will be measured during the lifespan of normal mice and mice overexpressing IGF-1 in myocytes: FVB/N, FVB.Igf-/-, FVB.Igf+/- and FVB.Igf+/+. By comparing distinct levels of IGF-1 in the heart, it might be feasible to demonstrate whether the IGF-1 system protects cells from the effects of time, thereby delaying myocyte aging and improving the myocardial response to pathologic loads in women.
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