Estrogen and oxidative stress: A novel mechanism that may increase the risk for cardiovascular disease in women.
Although early studies demonstrated that exogenous estrogen lowered a woman's risk of cardiovascular disease, recent trials indicate that HRT actually increases the risk of coronary heart disease or stroke. However, there is no clear explanation for this discrepancy. Is estrogen a helpful or a harmful hormone in terms of cardiovascular function? This review discusses some recent findings that propose a novel mechanism which may shed significant light upon this controversy. We propose that nitric oxide synthase (NOS) expressed within the vascular wall is a target of estrogen action. Under normal conditions in younger women, the primary product of estrogen action is NO, which produces a number of beneficial effects on vascular biology. As a woman ages, however, there is evidence for loss of important molecules essential for NO production (e.g., tetrahydrobiopterin, l-arginine). As these molecules are depleted, NOS becomes increasingly "uncoupled" from NO production, and instead produces superoxide, a dangerous reactive oxygen species. We propose that a similar uncoupling and reversal of estrogen response occurs in diabetes. Therefore, we propose that estrogen is neither "good" nor "bad", but simply stimulates NOS activity. It is the biochemical environment around NOS that will determine whether estrogen produces a beneficial (NO) or deleterious (superoxide) product, and can account for this dual and opposite nature of estrogen pharmacology. Further, this molecular mechanism is consistent with recent analyses revealing that HRT produces salutary effects in younger women, but mainly increases the risk of cardiovascular dysfunction in older postmenopausal women.
White
Richard E
RE
Department of Pharmacology & Toxicology, Medical College of Georgia, Augusta, GA 30912, United States. rwhite@mcg.edu
Gerrity
Ross
R
Barman
Scott A
SA
Han
Guichun
G
D002318:Cardiovascular Diseases / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D015914:Estrogen Replacement Therapy / Q000009:adverse effects; D004967:Estrogens / Q000378:metabolism*; D005260:Female; D006801:Humans; D009131:Muscle, Smooth, Vascular / Q000201:enzymology / Q000378:metabolism; D009569:Nitric Oxide / Q000096:biosynthesis / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000378:metabolism; D018384:Oxidative Stress; D013481:Superoxides / Q000378:metabolism
D004967:Estrogens; D013481:Superoxides; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase