Department of Basic Medical Sciences, University of Arizona College of Medicine, Phoenix, Arizona, USA.
Am J Physiol Heart Circ Physiol. 2011 Nov;301(5):H1882-90. doi: 10.1152/ajpheart.00446.2011. Epub 2011 Aug 19.
Dihydrotestosterone (DHT) attenuates cytokine-induced cyclooxygenase-2 (COX-2) in coronary vascular smooth muscle. Since hypoxia inducible factor-1α (HIF-1α) activation can lead to COX-2 production, this study determined the influence of DHT on HIF-1α and COX-2 following hypoxia or hypoxia with glucose deprivation (HGD) in the cerebral vasculature. COX-2 and HIF-1α levels were assessed via Western blot, and HIF-1α activation was indirectly measured via a DNA binding assay. Experiments were performed using cerebral arteries isolated from castrated male rats treated in vivo with placebo or DHT (18 days) followed by hypoxic exposure ex vivo (1% O(2)), cerebral arteries isolated from castrated male rats treated ex vivo with vehicle or DHT (10 or 100 nM; 18 h) and then exposed to hypoxia ex vivo (1% O(2)), or primary human brain vascular smooth muscle cells treated with DHT (10 nM; 6 h) or vehicle then exposed to hypoxia or HGD. Under normoxic conditions, DHT increased COX-2 (cells 51%; arteries ex vivo 31%; arteries in vivo 161%) but had no effect on HIF-1α. Following hypoxia or HGD, HIF-1α and COX-2 levels were increased; this response was blunted by DHT (cells HGD: -47% COX-2, -34% HIF-1α; cells hypoxia: -29% COX-2, -54% HIF-1α; arteries ex vivo: -37% COX-2; arteries in vivo: -35% COX-2) and not reversed by androgen receptor blockade. Hypoxia-induced HIF-1α DNA-binding was also attenuated by DHT (arteries ex vivo and in vivo: -55%). These results demonstrate that upregulation of COX-2 and HIF-1α in response to hypoxia is suppressed by DHT via an androgen receptor-independent mechanism.
二氢睾酮（DHT）可减弱冠状动脉血管平滑肌中环氧化酶-2（COX-2）的细胞因子诱导作用。由于缺氧诱导因子-1α（HIF-1α）的激活可导致 COX-2 的产生，因此本研究旨在确定 DHT 对缺氧或缺氧伴葡萄糖剥夺（HGD）后脑血管中 HIF-1α 和 COX-2 的影响。通过 Western blot 检测 COX-2 和 HIF-1α 水平，通过 DNA 结合测定间接测量 HIF-1α 的激活。实验采用体内给予安慰剂或 DHT（18 天）预处理后进行体外缺氧暴露（1% O2）的去势雄性大鼠分离的脑动脉、体外给予载体或 DHT（10 或 100 nM；18 h）预处理后进行体外缺氧暴露（1% O2）的去势雄性大鼠分离的脑动脉，或用 DHT（10 nM；6 h）或载体处理后进行缺氧或 HGD 处理的原代人脑血管平滑肌细胞进行。在常氧条件下，DHT 增加 COX-2（细胞 51%；离体动脉 31%；体内动脉 161%），但对 HIF-1α 无影响。缺氧或 HGD 后，HIF-1α 和 COX-2 水平增加；这种反应被 DHT 减弱（细胞 HGD：COX-2 减少 47%，HIF-1α 减少 34%；细胞缺氧：COX-2 减少 29%，HIF-1α 减少 54%；离体动脉：COX-2 减少 37%；体内动脉：COX-2 减少 35%），且雄激素受体阻断不能逆转。DHT 还减弱了缺氧诱导的 HIF-1α DNA 结合（离体和体内动脉：减少 55%）。这些结果表明，DHT 通过非雄激素受体依赖机制抑制缺氧诱导的 COX-2 和 HIF-1α 的上调。
