Estrogen receptor beta dependent attenuation of cytokine-induced cyclooxygenase-2 by androgens in human brain vascular smooth muscle cells and rat mesenteric arteries

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• 作者：Kristen L. Zuloaga ; Devin T. O&rsquo ; Connor ; Robert J. Handa ; Rayna J. Gonzales ; ^{rjgonzal@email.arizona.edu}
• 关键词：3伪-HSD ; 3 alpha hydroxysteroid dehydrogenase ; 3尾-diol ; 5伪-androstane-3尾 ; 17尾-diol ; 3尾-HSD ; 3 beta hydroxysteroid dehydrogenase ; 17尾-HSD ; 17 beta hydroxysteroid dehydrogenase ; Adiol ; 5伪-androstene-3尾 ; 17尾-diol ; AR ; androgen receptor ; COX-2 ; cycloox
• 刊名：Steroids
• 出版年：2012
• 期刊代码：142_0039128x
• 类别：bio
• 出版时间：July, 2012
• 卷：77
• 期：8-9
• 页码：835-844
• 文件大小：848 K

摘要

Androgens may provide protective effects in the vasculature under pathophysiological conditions. Our past studies have shown that dihydrotestosterone (DHT) decreases expression of cyclooxygenase-2 (COX-2) during cytokine, endotoxin, or hypoxic stimulation in human vascular smooth muscle cells, in an androgen receptor (AR)-independent fashion. Classically DHT is regarded as a pure AR agonist; however, it can be endogenously metabolized to 5伪-androstane-3尾, 17尾-diol (3尾-diol), which has recently been shown to be a selective estrogen receptor (ER尾) agonist. Therefore, we hypothesized that DHT鈥檚 anti-inflammatory properties following cytokine stimulation are mediated through ER尾. Using primary human brain vascular smooth muscle cells (HBVSMC), we tested whether DHT鈥檚 effect on IL-1尾 induced COX-2 expression was mediated via AR or ER尾. The metabolism of DHT to 3尾-diol is a viable pathway in HBVSMC since mRNA for enzymes necessary for the synthesis and metabolism of 3尾-diol [3alpha-hydroxysteroid dehydrogenase (HSD), 3尾-HSD, 17尾-HSD, CYP7B1] was detected. In addition, the expression of AR, ER伪, and ER尾 mRNA was detected. When applied to HBVSMC, DHT (10 nM; 18 h) attenuated IL-1尾-induced increases in COX-2 protein expression. The AR antagonist bicalutamide did not block DHT鈥檚 ability to reduce COX-2. Both the non-selective estrogen receptor antagonist ICI 182,780 (1 渭M) and the selective ER尾 antagonist PHTPP (1 渭M) inhibited the effect of DHT, suggesting that DHT actions are ER尾-mediated. In HBVSMC and in rat mesenteric arteries, 3尾-diol, similar to DHT, reduced cytokine-induced COX-2 levels. In conclusion, DHT appears to be protective against the progression of vascular inflammation through metabolism to 3尾-diol and activation of ER尾.