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

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

doi:10.1074/jbc.m707451200

Matthew J. Callaghan, Michael Brownlee + Show 5 more

Open Access

https://doi.org/10.1074/jbc.m707451200

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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 HIF1alpha 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. HIF1alpha modification by methylglyoxal reduced heterodimer formation and HIF1alpha 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.

Highlights

Ischemic tissue selectively recruits endothelial progenitor cells (EPCs)3 from the bone marrow compartment by up-regulating the chemokine stromal cell-derived factor-1 (SDF-1)
We evaluated the possible role of diabetes-induced intracellular superoxide formation in defective ischemia-induced neovascularization by using two complementary murine models: diabetic transgenic mice overexpressing manganese superoxide dismutase, the mitochondrial isoform of this enzyme, and diabetic WT mice treated with a cell-permeable superoxide dismutase/catalase mimetic, Mn-TBAP
Receptor and endothelial nitric-oxide synthase (eNOS) in Response to Hypoxia—After determining that hyperglycemia-induced methylglyoxal accumulation reduced the ability of ischemic tissue to generate appropriate levels of chemokine and growth factor signals, we evaluated the effects of hyperglycemia on the ability of endothelial progenitor cells to respond to the ischemiaspecific mobilizing signal SDF-1

Summary

Introduction

Ischemic tissue selectively recruits endothelial progenitor cells (EPCs)3 from the bone marrow compartment by up-regulating the chemokine stromal cell-derived factor-1 (SDF-1). The observed failure of diabetic animals to mobilize and recruit reparative progenitor cells in a peripheral wound model reflects both a failure of the ischemic tissue to generate appropriate levels of at least one chemokine signal, SDF-1␣, and a failure of progenitor cells to respond to ischemia-specific signals due in part to a decrease in eNOS activation [5].

Results

Conclusion