The overall purpose of the experiments in this proposal is to evaluate the role of androgens and estrogens in the development of ischemia heart disease (IHD) in males. To accomplish this objective, we will use a multifactorial approach. Studies have demonstrated diverse effects of gonadal steroids on specific parameters related to cardiovascular integrity, but the basic question of whether androgens or estrogens have deleterious or protective effects in IHD remains controversial. Thus, we will simultaneously employ rat models of arteriosclerosis, vascular reactivity and thromboembolism. In addition, the effects of the hormones on plasma lipid (TG, total cholesterol, HDL cholesterol) and apoprotein patterns in selected cases will be evaluated. The effect of hormonal manipulation will be qualitatively and quantitatively evaluated, so that both the nature of the effect and dose-dependency are determined. For each group of studies, the results will be examined for the likely net effect of the exogenous or endogenous steroid in ischemica heart disease. We do not necessarily expect that results in the three models will be in concordance: a specific manipulation might have opposite effects on thrombosis and vasoreactivity. It is to facilitate comparisons between models that the methods used are identical wherever possible. Some questions we expect to address in this final analysis are: i. Can either androgens or estrogens be considered general risk factors or protective agents in male IHD? ii. Is the observed sex difference in IHD attributed to the endocrine status of the male? iii. Is manipulation of the endocrine system, for example by anti-adnrogens, a potential therapeutic measure in male IHD. iv. Is endocrine manipulation especially deleterious or protective with respect to a specific aspect of IHD, for example thrombosis, but not to other aspects? The study will clarify the endocrine mechanisms of the higher incidence of IHD in males and suggest possible preventive or therapeutic measures. Furthermore, the studies should help greatly in clarifying the confusion in the literature regarding estrogens, androgens and gender in IHD in general as well as in specific aspects of IHD such as thromboembolism, lipoprotein metabolism, alteriosclerosis, and vasoreactivity.
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