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(Circulation. 1997;95:1378-1385.)
© 1997 American Heart Association, Inc.

Articles

Antioxidant Protection of LDL by Physiological Concentrations of 17ß-Estradiol

Requirement for Estradiol Modification

Glenn T. Shwaery, PhD; Joseph A. Vita, MD; John F. Keaney, Jr, MD

From the Evans Memorial Department of Medicine and Whitaker Cardiovascular Institute, Boston (Mass) University Medical Center.

Correspondence to John F. Keaney, Jr, MD, Whitaker Cardiovascular Institute, Room W507, Boston University Medical Center, 80 E Concord St, Boston, MA 02118. E-mail jkeaney{at}acs.bu.edu.

Background Exposure to estrogens reduces the risk for coronary artery disease and associated clinical events; however, the mechanisms responsible for these observations are not clear. Supraphysiological levels of estrogens act as antioxidants in vitro, limiting oxidation of low-density lipoprotein (LDL), an event implicated in atherogenesis. We investigated the conditions under which physiological concentrations of 17ß-estradiol (E₂) inhibit oxidative modification of LDL.

Methods and Results Plasma incubated with E₂ (0.1 to 100 nmol/L) for 4 hours yielded LDL that demonstrated a dose-related increase in resistance to oxidation by Cu²⁺ as measured by conjugated diene formation. This effect was dependent on plasma, because incubation of isolated LDL with E₂ at these concentrations in buffered saline produced no effect on Cu²⁺-mediated oxidation. Incubation of plasma with E₂ had no effect on LDL -tocopherol content or cholesteryl ester hydroperoxide formation during the 4-hour incubation. Plasma incubation with [³H]E₂ was associated with dose-dependent association of ³H with LDL. High-performance liquid chromatographic analysis of LDL derived from plasma incubated with [³H]E₂ indicated that the majority of the associated species were not detectable as authentic E₂ but as nonpolar forms of E₂ that were susceptible to base hydrolysis consistent with fatty acid esterification of E₂. Plasma-mediated association of E₂ and subsequent antioxidant protection was inhibited by 5,5'-dithio-bis(2-nitrobenzoic acid), an inhibitor of plasma acyltransferase activity.

Conclusions Exposure of LDL to physiological levels of E₂ in a plasma milieu is associated with enhanced resistance to Cu²⁺-mediated oxidation and incorporation of E₂ derivatives into LDL. This antioxidant capacity may be another means by which E₂ limits coronary artery disease in women.

Key Words: hormones • lipoproteins • women • antioxidants

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