Cardiovascular disease is the leading cause of morbidity and mortality in the elderly. As such, significant advancements in the understanding of atherogenesis in aging have emerged, yet little is known about how gender or sex hormones, and aging affect heart muscle function. Studies in rats and humans suggest that the cardiac myocyte loss, fibrosis, and reactive hypertrophy that occurs in the aging male heart is less pronounced in the female heart. Our preliminary investigations demonstrate that (1) male and female rat hearts express estrogen receptors predominantly of the beta subtype; (2) female rat hearts are more sensitive to the positive inotropic effect elicited by increases in extracellular calcium concentration and to the negative inotropic action of nifedipine; (3) male and female hearts show no difference in the response to ryanodine or in the relative content of myosin heavy chain; (4) female and estradiol-treated hearts exhibit greater contractility than male hearts; and (5) myocytes from aged rats have reduced peak L-type calcium current. This research proposal will test the hypothesis that aging-related changes in cardiac contractile function are delayed in female hearts because estrogen delays aging-induced alterations in calcium homeostasis. Ventricular cardiac myocytes will be isolated from 6,12,18, 24, and 30 month old rats (Fischer 344) of four populations: male, female, ovariectomized, and ovariectomized rats supplemented with 17 D-estradiol. The hypothesis will be addressed by generating pilot data to answer the following questions: (1) are there gender differences in aging-associated changes in L-type calcium current in cardiac myocytes? (2) are there gender differences in aging-associated changes in cardiac calcium transients in cardiac myocytes? and (3) are observed gender differences in aging-associated changes in calcium current and transients negated by ovariectomy, and are the effects of ovariectomy reversed by estradiol? The long-term goals of this project are to develop therapeutic strategies that might prevent aging-related changes in cardiac contractile function in both men and women. If our results suggest that estrogen can delay aging-related changes in cardiac calcium homeostasis, future studies would be aimed at identifying target genes for estrogen-induced cardioprotection, determining the role of ERalpha and ERbeta in the estrogen effects, and searching for estrogenic treatments with cardioprotective actions but with lower risk of adverse effects for men and women.
