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 respons ible for these observations are not clear. Supraphysiological levels o f estrogens act as antioxidants in vitro, limiting oxidation of low-de nsity lipoprotein (LDL), an event implicated in atherogenesis. We inve stigated 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 t o oxidation by Cu2+ as measured by conjugated diene formation. This ef fect 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 for mation during the 4-hour incubation. Plasma incubation with [H-3]E(2) was associated with dose-dependent association of H-3 with LDL. High-p erformance 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 o f E(2) that were susceptible to base hydrolysis consistent with fatty acid esterification of E(2), Plasma-mediated association of E(2) and s ubsequent antioxidant protection was inhibited by 5,5'-dithio-bis(2-ni trobenzoic acid), an inhibitor of plasma acyltransferase activity. Con clusions Exposure of LDL to physiological levels of E(2) in a plasma m ilieu is associated with enhanced resistance to Cu2+-mediated oxidatio n and incorporation of E(2) derivatives into LDL. This antioxidant cap acity may be another means by which E(2) limits coronary artery diseas e in women.