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

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Abstract
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 17β-estradiol (E 2 ) inhibit oxidative modification of LDL. Methods and Results Plasma incubated with E 2 (0.1 to 100 nmol/L) for 4 hours yielded LDL that demonstrated a dose-related increase in resistance to oxidation by Cu 2+ as measured by conjugated diene formation. This effect was dependent on plasma, because incubation of isolated LDL with E 2 at these concentrations in buffered saline produced no effect on Cu 2+ -mediated oxidation. Incubation of plasma with E 2 had no effect on LDL α-tocopherol content or cholesteryl ester hydroperoxide formation during the 4-hour incubation. Plasma incubation with [ 3 H]E 2 was associated with dose-dependent association of 3 H with LDL. High-performance liquid chromatographic analysis of LDL derived from plasma incubated with [ 3 H]E 2 indicated that the majority of the associated species were not detectable as authentic E 2 but as nonpolar forms of E 2 that were susceptible to base hydrolysis consistent with fatty acid esterification of E 2 . Plasma-mediated association of E 2 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 E 2 in a plasma milieu is associated with enhanced resistance to Cu 2+ -mediated oxidation and incorporation of E 2 derivatives into LDL. This antioxidant capacity may be another means by which E 2 limits coronary artery disease in women.