Antioxidant protection of LDL by physiological concentrations of 17 beta-estradiol - Requirement for estradiol modification

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 17 beta-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 Cu2+ 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 Cu2+-mediated oxidation. Incubation of plasma with E(2) had no effect on LDL alpha-tocopherol content or cholesteryl ester hydroperoxide formation during the 4-hour incubation. Plasma incubation with [H-3]E(2) was associated with dose-dependent association of H-3 with LDL. High-performance liquid chromatographic analysis of LDL derived from plasma incubated with [H-3]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 Cu2+-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.