TY - JOUR
T1 - Estrogen and oxidative stress
T2 - A novel mechanism that may increase the risk for cardiovascular disease in women
AU - White, Richard E.
AU - Gerrity, Ross
AU - Barman, Scott A.
AU - Han, Guichun
N1 - Funding Information:
We would like to thank our sources of support for this work: grants from the National Heart, Lung, and Blood Institute (HL-64779 and HL07389, R. White; HL-68026, S. Barman) and the American Heart Association (Scientist Development Grant, G. Han; Southeast Affiliate 0555149B, S. Barman). Sadly, we must report that our colleague, Dr. Ross Gerrity, passed away in July of 2008 due to diabetes-related coronary heart disease. We dedicate this article to his memory.
PY - 2010/11
Y1 - 2010/11
N2 - 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.
AB - 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.
KW - Coronary
KW - Estrogen
KW - Hormone replacement therapy
KW - Nitric oxide
KW - Superoxide
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U2 - 10.1016/j.steroids.2009.12.007
DO - 10.1016/j.steroids.2009.12.007
M3 - Article
C2 - 20060403
AN - SCOPUS:77955924308
SN - 0039-128X
VL - 75
SP - 788
EP - 793
JO - Steroids
JF - Steroids
IS - 11
ER -