Dihydrotestosterone attenuates HIF‐1alpha and COX‐2 in cerebral arteries following hypoxia.

Abstract

Vascular inflammation is under the control of several transcription factors, one of which is hypoxia inducible factor‐1 alpha (HIF‐1α). HIF‐1α activation can lead to the production of inflammatory mediators such as cyclooxygenase‐2 (COX‐2). This study determined the influence of dihydrotestosterone (DHT) on HIF‐1α and COX‐2 following hypoxia. COX‐2 and HIF‐1α protein levels were assessed in cerebral arteries isolated from castrated rats treated with DHT (3 wk) in vivo and exposed to normoxia or hypoxia (1%; 6h) ex vivo and in primary human brain vascular smooth muscle cells pretreated with vehicle or DHT (100nM; 18h) and exposed to hypoxia and glucose deprivation (1% O2; 0 or 6h). Under normoxic conditions, DHT increased COX‐2 levels but had no effect on HIF‐1α protein levels and HIF‐1α DNA‐binding was below the level of detection. Following hypoxia or hypoxia and glucose deprivation, HIF‐1α and COX‐2 levels were increased; this response was blunted in the presence of DHT. In addition, increases in HIF‐1α DNA‐binding following hypoxia (1%; 1h) were reversed by DHT. In conclusion, under hypoxic conditions, the blunted response of COX‐2 by DHT may involve HIF‐1α activation. In contrast, the effect of DHT to increase COX‐2 under normoxic conditions may be independent of the HIF‐1α pathway.AHA SDG RG, AHA Predoctoral Fellowship KO