Downregulation of CYP17A1 by 20-hydroxyecdysone: plasma progesterone and its vasodilatory properties.

Aim: To investigate the effect of 20-hydroxyecdysone on steroidogenic pathway genes and plasma progesterone, and its potential impact on vascular functions. Methods: Chimeric mice with humanized liver were treated with 20-hydroxyecdysone for 3 days, and hepatic steroidogenic pathway genes and plasma progesterone were measured by transcriptomics and GC-MS/MS, respectively. Direct effects on muscle and mesenteric arterioles were assessed by myography. Results: CYP17A1 was downregulated in 20-hydroxyecdysone-treated mice compared with untreated group (p = 0.04), with an insignificant increase in plasma progesterone. Progesterone caused vasorelaxation which was blocked by 60 mM KCl, but unaffected by nitric oxide synthase inhibition. Conclusion: In the short term, 20-hydroxyecdysone mediates CYP17A1 downregulation without a significant increase in plasma progesterone, which has a vasodilatory effect involving inhibition of voltage-dependent calcium channels, and the potential to enhance 20-hydroxyecdysone vasorelaxation.

Altered cyclooxygenase-1 and enhanced thromboxane receptor activities underlie attenuated endothelial dilatory capacity of omental arteries in obesity.

AIMS: Obesity is a risk factor for endothelial dysfunction, the severity of which is likely to vary depending on extent and impact of adiposity on the vasculature. This study investigates the roles of cyclooxygenase isoforms and thromboxane receptor activities in the differential endothelial dilatory capacities of arteries derived from omental and subcutaneous adipose tissues in obesity. MAIN METHODS: Small arteries were isolated from omental and subcutaneous adipose tissues obtained from consented morbidly obese patients (n = 65, BMI 45 ±â€¯6 kg m-2 [Mean ±â€¯SD]) undergoing bariatric surgery. Relaxation to acetylcholine was studied by wire myography in the absence or presence of indomethacin (10 µM, cyclooxygenase inhibitor), FR122047 (1 µM, cyclooxygenase-1 inhibitor), Celecoxib (4 µM, cyclooxygenase-2 inhibitor), Nω-Nitro-L-arginine methyl ester (L-NAME, 100 µM, nitric oxide synthase inhibitor) or combination of apamin (0.5 µM) and charybdotoxin (0.1 µM) that together inhibit endothelium-derived hyperpolarizing factor (EDHF). Contractions to U46619 (thromboxane A2 mimetic) were also studied. KEY FINDINGS: Acetylcholine relaxation was significantly attenuated in omental compared with subcutaneous arteries from same patients (p < 0.01). Indomethacin (p < 0.01) and FR122047 (p < 0.001) but not Celecoxib significantly improved the omental arteriolar relaxation. Cyclooxygenase-1 mRNA and U46619 contractions were both increased in omental compared with subcutaneous arteries (p < 0.05). L-NAME comparably inhibited acetylcholine relaxation in both arteries, while apamin+charybdotoxin were less effective in omental compared with subcutaneous arteries. SIGNIFICANCE: The results show that the depot-specific reduction in endothelial dilatory capacity of omental compared with subcutaneous arteries in obesity is in large part due to altered cyclooxygenase-1 and enhanced thromboxane receptor activities, which cause EDHF deficiency.