期刊
CELL CYCLE
卷 9, 期 1, 页码 75-79出版社
TAYLOR & FRANCIS INC
DOI: 10.4161/cc.9.1.10371
关键词
diabetes; neovascularization; vasculogenesis; HIF-1; HIF-1 alpha; hypoxia; DFO; methylglyoxal; p300
类别
资金
- National Institute of Diabetes and Digestive and Kidney Diseases [RO1-DK-074095]
- American Heart Association
- NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES [R01DK074095] Funding Source: NIH RePORTER
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-1 alpha (HIF-1 alpha), 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-1 alpha activity, not stability, is impaired in the high glucose environment. We demonstrate that high glucose-induced impairments in HIF-1 alpha transactivation persist even in the setting of constitutive HIF-1 alpha protein overexpression. Further, we show that high glucose-induced hydroxylation of the C-terminal transactivation domain of HIF-1 alpha (the primary pathway regulating HIF-1 alpha/p300 binding) does not alter HIF-1 alpha 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.
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