Circulation Research. 2003;93:170-177
Published online before print June 19, 2003, doi: 10.1161/01.RES.0000082334.17947.11
Published online before print June 19, 2003, doi: 10.1161/01.RES.0000082334.17947.11
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© 2003 American Heart Association, Inc.
Molecular Medicine |
Modulation of Antioxidant Enzyme Expression and Function by Estrogen
From the Medizinische Klinik und Poliklinik, Innere Medizin III (K.S., S.R., S.W., O.A., M.B., G.N.) and Klinik und Poliklinik für Gynäkologie (K.L.), Universitätskliniken des Saarlandes, Homburg/Saar, and Universitäts-Poliklinik Bonn (C.G.), Bonn, Germany.
Correspondence to Dr Georg Nickenig, Medizinische Klinik und Poliklinik, Innere Medizin III; Universitätskliniken des Saarlandes, D-66421 Homburg/Saar, Germany. E-mail nickenig{at}med-in.uni-sb.de
Oxidative stress plays a pivotal role in the pathogenesis of atherosclerosis and can be effectively influenced by radical scavenging enzyme activity and expression. The vasoprotective effects of estrogens may be related to antioxidative properties. Therefore, effects of 17ß-estradiol on production of reactive oxygen species and radical scavenging enzymes were investigated. 17ß-estradiol diminished angiotensin II–induced free radical production in vascular smooth muscle cells (DCF fluorescence laser microscopy). 17ß-estradiol time- and concentration-dependently upregulated manganese (MnSOD) and extracellular superoxide dismutase (ecSOD) expression (Northern and Western blotting) and enzyme activity (photometric assay). Nuclear run-on assays demonstrated that 17ß-estradiol increases MnSOD and ecSOD transcription rate. Half-life of MnSOD mRNA was not influenced, whereas ecSOD mRNA was stabilized by estrogen. Copper-zinc SOD, glutathione-peroxidase, and catalase were not affected by estrogen. Estrogen deficiency in ovariectomized mice induced a downregulation of ecSOD and MnSOD expression, which was associated with increased production of vascular free radicals and prevented by estrogen replacement or treatment with PEG-SOD. In humans, increased estrogen levels led to enhanced ecSOD and MnSOD expression in circulating monocytes. Estrogen acts antioxidative at least to some extent via stimulation of MnSOD and ecSOD expression and activity, which may contribute to its vasoprotective effects.
Key Words: estrogen • superoxide dismutase • oxidative stress • atherosclerosis
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