HIF-1α dysfunction in diabetes

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.

Akt/hypoxia-inducible factor-1α signaling deficiency compromises skin wound healing in a type 1 diabetes mouse model

“…High blood glucose levels in diabetic mice decrease HIF-1 activity and impair diabetic wound healing, which is closely correlated with decreased Akt, HIF-1α and downstream signaling levels. A previous study has shown that high glucose concentrations lead to increased levels of hyperoxide, inducing the accumulation of pyruvaldehyde within the cells, and decreasing the protein levels and the transcriptional activity of HIF-1α (25). The present experiments showed that Akt expression increased during wound formation, which stimulated the expression of HIF-1α and downstream genes, with the expression reaching a peak on days 3 and 7.…”

Neoangiogenesis is Reduced in Chronic Tendinopathies and Type 2 Diabetic Patients

“…Moreover, in vitro experiments show that fibroblasts from diabetic mice exhibit a sevenfold impairment in VEGF production in response to hypoxia, compared with wild-type fibroblasts (12). Both fibroblasts isolated from type 2 diabetic patients, and normal fibroblasts exposed chronically to high glucose, are defective in their capacity to upregulate VEGF expression in response to hypoxia (13). Several mechanisms participate in the downregulation of VEGF expression, such as Advanced Glycation End Products, and a variety of growth factors and inflammatory cytokines.…”

Progenitor Cell Dysfunctions Underlie Some Diabetic Complications

“…30,49,85,86 Diabetes causes the overproduction of superoxide anion and the accumulation of glycolytic metabolites, such as methylglyoxal. 87 This alteration prevents the stabilization and activation of HIF, preventing HIF-mediated activation of vascular endothelial growth factor and SDF1 and resulting in impaired progenitor homing and poor neovascularization 50,88 (Figure 2). Current literature suggests that the impaired recruitment of progenitors after diabetic injury contributes to decreased neovascularization and deficiencies in healing.…”