Osterlund KL, Handa RJ, Gonzales RJ. Dihydrotestosterone alters cyclooxygenase-2 levels in human coronary artery smooth muscle cells. Am J Physiol Endocrinol Metab 298: E838 -E845, 2010. First published January 26, 2010; doi:10.1152/ajpendo.00693.2009.-Both protective and nonprotective effects of androgens on the cardiovascular system have been reported. Our previous studies show that the potent androgen receptor (AR) agonist dihydrotestosterone (DHT) increases levels of the vascular inflammatory mediator cyclooxygenase (COX)-2 in rodent cerebral arteries independent of an inflammatory stimulus. Little is known about the effects of androgens on inflammation in human vascular tissues. Therefore, we tested the hypothesis that DHT alters COX-2 levels in the absence and presence of induced inflammation in primary human coronary artery smooth muscle cells (HCASMC). Furthermore, we tested the ancillary hypothesis that DHT's effects on COX-2 levels are AR-dependent. Cells were treated with DHT (10 nM) or vehicle for 6 h in the presence or absence of LPS or IL-1␤. Similar to previous observations in rodent arteries, in HCASMC, DHT alone increased COX-2 levels compared with vehicle. This effect of DHT was attenuated in the presence of the AR antagonist bicalutamide. Conversely, in the presence of LPS or IL-1␤, increases in COX-2 were attenuated by cotreatment with DHT. Bicalutamide did not affect this response, suggesting that DHTinduced decreases in COX-2 levels occur independent of AR stimulation. Thus we conclude that DHT differentially influences COX-2 levels under physiological and pathophysiological conditions in HCASMC. This effect of DHT on COX-2 involves AR-dependent andindependent mechanisms, depending on the physiological state of the cell. vascular smooth muscle; interleukin-1␤; lipopolysaccharide; inflammation; androgen PRECLINICAL AND CLINICAL RESEARCH suggests that vascular inflammation is a critical regulator in the etiology and progression of cardiovascular disease that, if not treated or managed, can eventually lead to fatal clinical end points, such as stroke and myocardial infarction. Clinical data consistently show that cardiovascular disease is more prevalent in men than in premenopausal women (39). Numerous studies have focused on the role of estrogens in contributing to the sex-related disparities in cardiovascular disease, but the cardiovascular actions of androgens are not well understood. Among the few documented studies, there is disagreement as to whether androgens exacerbate or beneficially contribute to the development and progression of cardiovascular disease. Because chronic vascular inflammation contributes significantly to the pathogenesis of cardiovascular diseases (13,31,37), it is important to investigate the role of androgens under normal and pathophysiological conditions.During vascular inflammation, monocytes and macrophages penetrate the vessel wall and produce inflammatory cytokines (34), such as interleukin-1␤ (IL-1␤), leading to activation of NF-B, a transcription factor for i...

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