Published online before print September 29, 2005, doi: 10.1161/01.RES.0000188212.57180.55
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Submitted on April 6, 2005
Revised on September 14, 2005
Accepted on September 19, 2005
Progesterone Antagonizes the Vasoprotective Effect of Estrogen on Antioxidant Enzyme Expression and Function
Kerstin Wassmann *;
From the Klinik für Innere Medizin III, Universitätsklinikum des Saarlandes, Homburg/Saar, Germany.
* To whom correspondence should be addressed. E-mail: wassmann{at}med-in.uni-sb.de.
Oxidative stress plays an important role in the pathogenesis of atherosclerosis and can be effectively influenced by radical scavenging enzymes. Estrogens exert antioxidative effects in the vasculature; however, cotreatment with progesterone may abrogate the vasoprotective effects of estrogen. Therefore, the effects of progesterone on the production of reactive oxygen species (ROS) and expression and function of antioxidant enzymes were investigated in cultured vascular smooth muscle cells (VSMCs) and vascular tissue of mice. Progesterone time- and concentration-dependently downregulated extracellular superoxide dismutase (ecSOD) and manganese superoxide dismutase (MnSOD) expression and enzyme activity and reversed 17
-estradiol-induced overexpression of ecSOD and MnSOD in VSMCs. Nuclear run-on assays revealed that progesterone decreases MnSOD and ecSOD transcription rates. Consequently, progesterone increased ROS release in VSMCs that was prevented by concomitant treatment with 17-estradiol. Estrogen deficiency in ovariectomized mice was associated with an increase in vascular superoxide release and NADPH oxidase activity. Estrogen replacement prevented this increase, whereas progesterone substitution enhanced ROS production and NADPH oxidase activity. The modulation of superoxide release coincided with decreased expression of ecSOD and MnSOD and upregulation of the p22phox and p67phox subunits of the NADPH oxidase complex in progesterone-treated animals. Furthermore, administration of progesterone to ovariectomized mice treated with 17-estradiol abrogated the antioxidative effects of estrogen. Progesterone antagonizes the vasoprotective effects of estrogen on ecSOD and MnSOD expression and increases NADPH oxidase activity. These findings may in part explain why hormone replacement therapy with estrogen plus progesterone displayed no beneficial effect on cardiovascular event rates in the prospective clinical trials.
Key words: progesterone • estrogen • superoxide dismutase • oxidative stress • atherosclerosis
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