HIF-1α dysfunction in diabetes

Hariharan Thangarajah, Ivan N. Vial, Raymon H. Grogan, Dachun Yao, Yubin Shi, Michael Januszyk, Robert D. Galiano, Edward I. Chang, Michael G. Galvez, Jason P. Glotzbach, Victor W. Wong, Michael Brownlee, Geoffrey C. Gurtner

Research output: Contribution to journalReview article

103 Scopus citations

Abstract

Diabetic wounds are a significant public health burden, with slow or nonhealing diabetic foot ulcers representing the leading cause of non-traumatic lower limb amputation in developed countries. These wounds heal poorly as a result of compromised blood vessel formation in response to ischemia. We have recently shown that this impairment in neovascularization results from a high glucoseinduced defect in transactivation of hypoxia-inducible factor-1a (HIF-1α), the transcription factor regulating vascular endothelial growth factor (VEGF) expression. HIF-1 dysfunction is the end result of reactive oxygen species-induced modification of its coactivator p300 by the glycolytic metabolite methylglyoxal. Use of the iron chelator-antioxidant deferoxamine (DFO) reversed these effects and normalized healing of humanized diabetic wounds in mice. Here, we present additional data demonstrating that HIF-1α activity, not stability, is impaired in the high glucose environment. We demonstrate that high glucose-induced impairments in HIF-1a transactivation persist even in the setting of constitutive HIF-1α protein overexpression. Further, we show that high glucose-induced hydroxylation of the C-terminal transactivation domain of HIF-1α (the primary pathway regulating HIF-1α/p300 binding) does not alter HIF-1α activity. We extend our study of DFO's therapeutic efficacy in the treatment of impaired wound healing by demonstrating improvements in tissue viability in diabetic mice with DFOinduced increases in VEGF expression and vascular proliferation. Since DFO has been in clinical use for decades, the potential of this drug to treat a variety of ischemic conditions in humans can be evaluated relatively quickly.

Original languageEnglish (US)
Pages (from-to)75-79
Number of pages5
JournalCell Cycle
Volume9
Issue number1
DOIs
StatePublished - Jan 1 2010

Keywords

  • DFO
  • Diabetes
  • HIF-1
  • HIF-1α
  • Hypoxia
  • Methylglyoxal
  • Neovascularization
  • Vasculogenesis
  • p300

ASJC Scopus subject areas

  • Molecular Biology
  • Developmental Biology
  • Cell Biology

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    Thangarajah, H., Vial, I. N., Grogan, R. H., Yao, D., Shi, Y., Januszyk, M., Galiano, R. D., Chang, E. I., Galvez, M. G., Glotzbach, J. P., Wong, V. W., Brownlee, M., & Gurtner, G. C. (2010). HIF-1α dysfunction in diabetes. Cell Cycle, 9(1), 75-79. https://doi.org/10.4161/cc.9.1.10371