Dihydrotestosterone attenuates hypoxia inducible factor-1α and cyclooxygenase-2 in cerebral arteries during hypoxia or hypoxia with glucose deprivation

Kristen L. Zuloaga, Rayna J. Gonzales

Research output: Contribution to journalArticle

13 Scopus citations

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% O2), 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% O2), 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.

Original languageEnglish (US)
Pages (from-to)H1882-H1890
JournalAmerican Journal of Physiology - Heart and Circulatory Physiology
Volume301
Issue number5
DOIs
StatePublished - Nov 1 2011

Keywords

  • Androgen
  • Inflammation
  • Vascular smooth muscle

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

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