Dihydrotestosterone alters cyclooxygenase-2 levels in human coronary artery smooth muscle cells

Abstract

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...

The influence of acute resistance exercise on cyclooxygenase-1 and -2 activity and protein levels in human skeletal muscle

“…COX-2 membranes were not stripped between anti-COX-2 and GAPDH incubations. COX-2 antibody specificity was verified with LPS-stimulated RAW 264.7 mouse macrophage cell lysate (Santa Cruz Biotechnology, Santa Cruz, CA) in a previous study (18). COX-1 antibody specificity was verified using human coronary vascular smooth muscle lysate [ Fig.…”

“…An aliquot of the homogenized sample that was used to determine the levels of COX-1 and COX-2 protein was also examined using standard immunoblotting methods (18). Human muscle samples were homogenized as described above.…”

Testosterone: a vascular hormone in health and disease

“…Interestingly, under normal conditions without proinflammatory stimulation, DHT alone increased COX2 levels compared with the vehicle and AR antagonism attenuated the response. The authors suggest that DHT differentially effects COX2 levels under physiological and pathophysiological conditions in human coronary artery smooth muscle cells and via AR-dependent andindependent mechanisms influenced by the physiological state of the cell (Osterlund et al 2010). DHT was also shown to suppress hypoxia-induced upregulation of COX2 by inhibiting hypoxia-inducible factor 1a (HIF1a (HIF1A)) DNA binding and subsequent transcription of the COX2 gene in primary human brain VSMCs (Zuloaga & Gonzales 2011).…”

“…Using the non-aromatisable androgen DHT, Osterlund et al (2010) demonstrated that human coronary artery smooth muscle cells (HCASMCs) attenuate their increased expression of the inflammatory mediator COX2 under inflammatory conditions (LPS or IL1b) when co-treated with DHT. This effect of DHT was not altered by AR antagonism with bicalutamide.…”

Regulated expression of the prostacyclin receptor (IP) gene by androgens within the vasculature: Combined role for androgens and serum cholesterol

“…COX2 expression is upregulated in response to DHT in periovulatory granulosa cells, where androgens were found to directly regulate the COX2 gene through an AR-dependent mechanism [60]. Within the vasculature, DHT increases COX2 expression in human coronary artery smooth muscle cells and, while not measured directly, that study suggested that DHT might lead to increased prostacyclin levels [61]. Consistent with that suggestion, testosterone leads to an enhanced vasodilatory response in diabetic rabbits compared with control animals and occurs, in part, due to increased COX2-derived prostacyclin synthesis [62].…”