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J. Biol. Chem., Vol. 283, Issue 16, 10930-10938, April 18, 2008

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Decreasing Intracellular Superoxide Corrects Defective Ischemia-induced New Vessel Formation in Diabetic Mice^*

Daniel J. Ceradini¹, Dachun Yao¹, Raymon H. Grogan, Matthew J. Callaghan, Diane Edelstein, Michael Brownlee², and Geoffrey C. Gurtner

From the Department of Surgery, Stanford University School of Medicine, Stanford, California 94305-5148 and the JDRF International Center for Diabetic Complications Research, Albert Einstein College of Medicine, Bronx, New York 10461-1602

Tissue ischemia promotes vasculogenesis through chemokine-induced recruitment of bone marrow-derived endothelial progenitor cells (EPCs). Diabetes significantly impairs this process. Because hyperglycemia increases reactive oxygen species in a number of cell types, and because many of the defects responsible for impaired vasculogenesis involve HIF1-regulated genes, we hypothesized that HIF1 function is impaired in diabetes because of reactive oxygen species-induced modification of HIF1 by the glyoxalase 1 (GLO1) substrate methylglyoxal. Decreasing superoxide in diabetic mice by either transgenic expression of manganese superoxide dismutase or by administration of an superoxide dismutase mimetic corrected post-ischemic defects in neovascularization, oxygen delivery, and chemokine expression, and normalized tissue survival. In hypoxic fibroblasts cultured in high glucose, overexpression of GLO1 prevented reduced expression of both the EPC mobilizing chemokine stromal cell-derived factor-1 (SDF-1) and of vascular epidermal growth factor, which modulates growth and differentiation of recruited EPCs. In hypoxic EPCs cultured in high glucose, overexpression of GLO1 prevented reduced expression of both the SDF-1 receptor CXCR4, and endothelial nitric-oxide synthase, an enzyme essential for EPC mobilization. HIF1 modification by methylglyoxal reduced heterodimer formation and HIF1 binding to all relevant promoters. These results provide a basis for the rational design of new therapeutics to normalize impaired ischemia-induced vasculogenesis in patients with diabetes.

Received for publication, September 5, 2007 , and in revised form, January 7, 2008.

^* This work was supported by NIDDK, National Institutes of Health Grants R01 DK74153-01 (to M. B.) and R01 DK74095-01 (to G. G.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Both authors contributed equally to the work.

² To whom correspondence should be addressed: F-531, 1300 Morris Park Ave., Bronx NY 10461. Tel.: 718-430-3636; Fax: 718-430-8570; E-mail: brownlee{at}aecom.yu.edu.

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