on May 19, 2005
Published online before print May 19, 2005, doi: 10.1161/01.ATV.0000170827.16296.6e
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Submitted on December 8, 2004
Accepted on May 9, 2005
Regulation of Xanthine Oxidoreductase Protein Expression by Hydrogen Peroxide and Calcium
J. Scott McNally ;
From the Division of Cardiology (J.S.M., A.S., S.D., D.G.H.), Molecular and Systems Pharmacology Program (J.S.M., D.G.H.), Emory University, Atlanta, Ga; the Atlanta Veterans Hospital Medical Center, Atlanta, Ga; and the Department of Medicine (H.C.), University of Chicago, Ill.
* To whom correspondence should be addressed. E-mail: dharr02{at}emory.edu.
Objective--We have previously demonstrated that endothelial xanthine oxidase (XO) levels are dependent on the NADPH oxidase. We postulated that H2O2 may modulate the irreversible conversion of xanthine dehydrogenase (XDH) to XO and sought to examine mechanisms involved.
Methods and Results--H2O2 (100 µmol/L) decreased bovine aortic endothelial cell (BAEC) XDH protein expression, and metabolic labeling studies indicated that H2O2 stimulated conversion of XDH to XO. The decline in XDH was mimicked by the reactive oxygen species (ROS) generating compounds SIN-1 and Menadione, as well as by stimulating BAECs with angiotensin II (200 nmol). BAPTA-AM prevented the decline in XDH by H2O2, indicating that it was calcium-dependent. In keeping with calcium acting downstream of H2O2, the calcium ionophore A23187 (1 µmol/L) caused XDH-to-XO conversion, and this was not prevented by the antioxidants. In addition, XDH-to-XO conversion was blocked by 2-APB and NO donors and induced by thapsigargin and 3M3-fetal bovine serum, implicating phospholipase C and endoplasmic reticulum calcium stores in this process.
Conclusions--Endothelial XO and XDH expression are strongly dependent on H2O2 and calcium. Stimulation of XDH conversion to XO may represent a feed-forward mechanism whereby H2O2 can stimulate further production of ROS.
Key words: calcium • hydrogen peroxide • reactive oxygen species • vascular endothelium • xanthine oxidoreductase
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