Decreasing intracellular superoxide corrects defective ischemia-induced new vessel formation in diabetic mice

Daniel J. Ceradini, Dachun Yao, Raymon H. Grogan, Matthew J. Callaghan, Diane Edelstein, Michael Brownlee, Geoffrey C. Gurtner

Research output: Contribution to journalArticle

171 Scopus citations

Abstract

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 HIF1α 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. HIF1α modification by methylglyoxal reduced heterodimer formation and HIF1α 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.

Original languageEnglish (US)
Pages (from-to)10930-10938
Number of pages9
JournalJournal of Biological Chemistry
Volume283
Issue number16
DOIs
StatePublished - Apr 18 2008

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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    Ceradini, D. J., Yao, D., Grogan, R. H., Callaghan, M. J., Edelstein, D., Brownlee, M., & Gurtner, G. C. (2008). Decreasing intracellular superoxide corrects defective ischemia-induced new vessel formation in diabetic mice. Journal of Biological Chemistry, 283(16), 10930-10938. https://doi.org/10.1074/jbc.M707451200