Estrogen modulates xanthine dehydrogenase/xanthine oxidase activity by a receptor-independent mechanism.
Hypoxia causes up-regulation and activation of xanthine dehydrogenase/xanthine oxidase (XDH/XO) in vitro and in the lungs in vivo. This up-regulation, and the likely corresponding production of reactive oxygen species, may underlie the pathogenesis of an array of disorders. Thus, compounds that prevent hypoxia-induced increase in XDH/XO activity may provide a therapeutic strategy in such disorders. The antioxidant properties of estrogens have been demonstrated in several studies. However, the effect of these compounds on XDH/XO has not been explored previously. The aim of this study was to investigate the effects of estrogen on hypoxia-induced increase in XDH/XO activity. Rat pulmonary artery microvascular endothelial cells were exposed to normoxia or hypoxia in the presence or absence of 17beta- or 17alpha-estradiol. The XDH/XO enzyme and gene promoter activities were measured in different groups of cells. Hypoxia caused a twofold increase in XDH/XO enzymatic and promoter activity. Either of the estradiol stereoisomers prevented the hypoxia-induced increase in XDH/XO enzymatic activity, but not the promoter activity. ICI 182,780, an antagonist of the estrogen receptor, failed to block the inhibitory effect of estradiol on XDH/XO. In conclusion, 17alpha- and 17beta-estradiol modulate the hypoxia-induced regulation of XDH/XO activity at a posttranscriptional level by a receptor-independent mechanism.
Pulmonary and Critical Care Division, Tupper Research Institute, Tufts-New England Medical Center, Tufts University School of Medicine, Boston, MA, USA.
Rohit
R
Budhiraja
Usamah S
US
Kayyali
Mallik
M
Karamsetty
Michael
M
Fogel
Nicholas S
NS
Hill
Roger
R
Chalkley
Geraldine A
GA
Finlay
Paul M
PM
Hassoun
D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D015153:Blotting, Western; D002478:Cells, Cultured; D004591:Electrophoresis, Polyacrylamide Gel; D004730:Endothelium, Vascular / Q000473:pathology; D004958:Estradiol / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D004965:Estrogen Antagonists / Q000494:pharmacology; D004967:Estrogens / Q000378:metabolism*; D000077267:Fulvestrant; D015971:Gene Expression Regulation, Enzymologic; D000860:Hypoxia; D008833:Microcirculation / Q000166:cytology; D011233:Precipitin Tests; D011401:Promoter Regions, Genetic; D011651:Pulmonary Artery / Q000473:pathology; D012323:RNA Processing, Post-Transcriptional; D051381:Rats; D017382:Reactive Oxygen Species; D015854:Up-Regulation; D014968:Xanthine Dehydrogenase / Q000378:metabolism*; D014969:Xanthine Oxidase / Q000378:metabolism*
D000975:Antioxidants; D004965:Estrogen Antagonists; D004967:Estrogens; D017382:Reactive Oxygen Species; D000077267:Fulvestrant; D004958:Estradiol; D014968:Xanthine Dehydrogenase; D014969:Xanthine Oxidase