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HIF-1alpha dysfunction in diabetes.
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
Geoffrey Gurtner on 3/31/2010
Cell cycle (Georgetown, Tex.)
Volume : Pages
9 : 75 - 79
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
Neuropathy & Neurocognition
E1A binding protein p300
hypoxia inducible factor 1, alpha subunit
Notch gene homolog 1, (Drosophila)
vascular endothelial growth factor A
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Please acknowledge all posters, manuscripts or scientific materials that were generated in part or whole using funds from the Diabetic Complications Consortium(DiaComp) using the following text:
Financial support for this work provided by the NIDDK Diabetic Complications Consortium (RRID:SCR_001415, www.diacomp.org), grants DK076169 and DK115255
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