title: Dihydrotestosterone attenuates hypoxia inducible factor-1α and cyclooxygenase-2 in cerebral arteries during hypoxia or hypoxia with glucose deprivation.
abstract: 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.
authors.affiliation: Department of Basic Medical Sciences, University of Arizona College of Medicine, Phoenix, Arizona, USA.
authors.forename: Kristen L
authors.initials: KL
authors.lastname: Zuloaga
authors.forename: Rayna J
authors.initials: RJ
authors.lastname: Gonzales
mesh_terms: D000726:Androgen Antagonists / Q000494:pharmacology; D000818:Animals; D015687:Cell Hypoxia; D002536:Cerebral Arteries / Q000187:drug effects* / Q000201:enzymology; D051546:Cyclooxygenase 2 / Q000378:metabolism*; D013196:Dihydrotestosterone / Q000008:administration & dosage*; D004343:Drug Implants; D005947:Glucose / Q000172:deficiency*; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D018836:Inflammation Mediators / Q000378:metabolism; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000201:enzymology; D032389:Myocytes, Smooth Muscle / Q000187:drug effects* / Q000201:enzymology; D009919:Orchiectomy; D051381:Rats; D017208:Rats, Wistar; D011944:Receptors, Androgen / Q000187:drug effects / Q000378:metabolism; D046509:Tissue Culture Techniques
chemical_list: C410798:AR protein, human; D000726:Androgen Antagonists; D004343:Drug Implants; C497442:HIF1A protein, human; C497444:Hif1a protein, rat; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D018836:Inflammation Mediators; D011944:Receptors, Androgen; D013196:Dihydrotestosterone; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; C489691:Ptgs2 protein, rat; D005947:Glucose