HIF-1alpha dysfunction in diabetes

• Published in: Cell cycle (Georgetown, Tex.) Tex.), 2010-01, Vol.9 (1), p.75-79
• Main Authors: Thangarajah, Hariharan, Vial, Ivan N, Grogan, Raymon H, Yao, Dachun, Shi, Yubin, Januszyk, Michael, Galiano, Robert D, Chang, Edward I, Galvez, Michael G, Glotzbach, Jason P, Wong, Victor W, Brownlee, Michael, Gurtner, Geoffrey C
• Format: Article
• Language: English
• Subjects: Animals; Deferoxamine - therapeutic use; Diabetes Mellitus - drug therapy; Diabetes Mellitus - metabolism; Humans; Hypoxia - physiopathology; Hypoxia-Inducible Factor 1, alpha Subunit - metabolism; Mice; Neovascularization, Pathologic - drug therapy; Neovascularization, Pathologic - metabolism; Siderophores - therapeutic use; Vascular Endothelial Growth Factor A - metabolism
• ISSN: 1551-4005

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.