The role of estrogens in modulating myocardial adaptation and function with aging has not been adequately explored. However, estrogen is likely an important cardiac regulator as ovariectomy in rats leads to reductions in heart size and function. Changes in alpha and beta myosin heavy chains (MHC) and other enzymes occur with aging and estrogen depletion but the role of estrogen or the associated mechanisms have not been ascertained. In our recent studies with cardiomyocytes in culture, estrogen increased the levels of protein kinase C (PKC) and myosin ATPase activity. In addition, a decline in these same enzyme activities was observed in myocardial fractions from rats aged 8-18 months or in hearts from ovariectomized young rats. It is therefore hypothesized that estrogens are important for regulating the synthesis of key signaling and contractile proteins in cardiomyocytes and that age related decreases in estrogens or estrogen-receptor function may contribute to change in cardiac adaptability. This hypothesis will be tested in cardiomyocytes isolated from female rats of various ages.
Specific aims are to test the hypotheses that: i) myocardial estrogen receptor density and nuclear/cytosolic compartmentation change with aging, ii) age affects the ability of estrogen to modulate estrogen receptor distribution or density, iii) the levels and distribution of PKC and MHC isoenzymes are altered with aging, and iv) age affects the ability of estrogen to modulate PKC and MHC isoenzymes in cultured cardiomyocytes. The results of this investigation will provide direct mechanistic information on the effects of estrogen on cardiomyocyte adaptation in the aging process. Protein kinase C and MHC have been strongly linked to various cardiac hypertrophies and therefore an understanding in changes of these isoenzymes may have importance in treating cardiac myopathies as well as providing evidence that estrogen replacement may be beneficial to maintain cardiomyocyte function in aging females.
