HIF-1alpha dysfunction in diabetes.
Authors Thangarajah H, Vial IN, Grogan RH, Yao D, Shi Y, Januszyk M, Galiano RD, Chang
EI, Galvez MG, Glotzbach JP, Wong VW, Brownlee M, Gurtner GC
Submitted By Geoffrey Gurtner on 3/31/2010
Status Published
Journal Cell cycle (Georgetown, Tex.)
Year 2010
Date Published 1/1/2010
Volume : Pages 9 : 75 - 79
PubMed Reference 20016290
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
glucose-induced defect in transactivation of hypoxia-inducible factor-1alpha
(HIF-1alpha), 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-1alpha
activity, not stability, is impaired in the high glucose environment. We
demonstrate that high glucose-induced impairments in HIF-1alpha transactivation
persist even in the setting of constitutive HIF-1alpha protein overexpression.
Further, we show that high glucose-induced hydroxylation of the C-terminal
transactivation domain of HIF-1alpha (the primary pathway regulating
HIF-1alpha/p300 binding) does not alter HIF-1alpha 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 DFO-induced
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.

Investigators with authorship
Geoffrey GurtnerStanford University


Ep300E1A binding protein p300
Hif1ahypoxia inducible factor 1, alpha subunit
Notch1Notch gene homolog 1, (Drosophila)
Vegfavascular endothelial growth factor A