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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2005;25:1623.)
© 2005 American Heart Association, Inc.

Vascular Biology

Regulation of Xanthine Oxidoreductase Protein Expression by Hydrogen Peroxide and Calcium

J. Scott McNally; Archana Saxena; Hua Cai; Sergey Dikalov; David G. Harrison

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.

Correspondence to David G. Harrison, Division of Cardiology, Emory University, 101 Woodruff Cir, WMB 319, Atlanta, GA 30322. 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/L). 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 M-3M3FBS, 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.

In this study we found that H₂O₂-dependent calcium release from the ER caused conversion of XDH to XO, and that this was prevented by nitric oxide. This may represent a feed-forward mechanism in many disease processes whereby H₂O₂ can stimulate further ROS production through XDH-to-XO conversion.

Key Words: calcium • hydrogen peroxide • reactive oxygen species • vascular endothelium • xanthine oxidoreductase

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