HIF-1alpha dysfunction in diabetes.
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.
Thangarajah
Hariharan
H
Department of Surgery, Stanford University School of Medicine, Stanford, CA, USA.
Vial
Ivan N
IN
Grogan
Raymon H
RH
Yao
Dachun
D
Shi
Yubin
Y
Januszyk
Michael
M
Galiano
Robert D
RD
Chang
Edward I
EI
Galvez
Michael G
MG
Glotzbach
Jason P
JP
Wong
Victor W
VW
Brownlee
Michael
M
Gurtner
Geoffrey C
GC
D000818:Animals; D003676:Deferoxamine / Q000627:therapeutic use; D003920:Diabetes Mellitus / Q000188:drug therapy / Q000378:metabolism*; D006801:Humans; D000860:Hypoxia / Q000503:physiopathology; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D051379:Mice; D009389:Neovascularization, Pathologic / Q000188:drug therapy / Q000378:metabolism; D017262:Siderophores / Q000627:therapeutic use; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D017262:Siderophores; D042461:Vascular Endothelial Growth Factor A; D003676:Deferoxamine