Estrogens are known to protect postmenopausal women from heart disease. An extraordinary range of beneficial effects have been associated with estrogens and the range of mechanisms appear to be equally broad. One overlooked mechanism of estrogen protection is its function as an antioxidant. We have established that estrogen selectively protects high density lipoprotein (LDL) from oxidation in vitro and have preliminary evidence that his mechanism is operational in vivo. The antioxidant protection of HDL is predicted to preserve the antiatherogenic functions of HDL. A mechanism for this selective antioxidant protection of HDL is proposed and will be tested. Furthermore, we hypothesize that estrogen protects from oxidant stress at the cellular level, reducing the inflammatory response to oxidized lipids. To establish the importance of antioxidant actions of strong we propose to 1) confirm that a direct relationship exists between estrone-mediated anti antioxidant protection of HDL seen in vitro is operational in vivo; 3) test the hypothesis that estrogen modulates inflammatory components of atherosclerosis by inhibiting lipid peroxidation and stimulating an autoimmune response. Successful completion of the proposed studies will enhance our understanding of the mechanism of action of estrogens in protecting from heart disease and will contribute useful information for the design of therapeutic selective estrogen receptor modulators (SERMs).
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