TY - JOUR
T1 - Estrogen Modulates Xanthine Dehydrogenase/Xanthine Oxidase Activity by a Receptor-Independent Mechanism
AU - Budhiraja, Rohit
AU - Kayyali, Usamah S.
AU - Karamsetty, Mallik
AU - Fogel, Michael
AU - Hill, Nicholas S.
AU - Chalkley, Roger
AU - Finlay, Geraldine A.
AU - Hassoun, Paul M.
PY - 2003/12
Y1 - 2003/12
N2 - 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 17β- or 17α-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, 17α- and 17β-estradiol modulate the hypoxia-induced regulation of XDH/XO activity at a posttranscriptional level by a receptor-independent mechanism.
AB - 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 17β- or 17α-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, 17α- and 17β-estradiol modulate the hypoxia-induced regulation of XDH/XO activity at a posttranscriptional level by a receptor-independent mechanism.
UR - http://www.scopus.com/inward/record.url?scp=0345690186&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0345690186&partnerID=8YFLogxK
U2 - 10.1089/152308603770380007
DO - 10.1089/152308603770380007
M3 - Article
C2 - 14588143
AN - SCOPUS:0345690186
SN - 1523-0864
VL - 5
SP - 705
EP - 711
JO - Antioxidants and Redox Signaling
JF - Antioxidants and Redox Signaling
IS - 6
ER -