Hypoxia-inducible Factor-1α in Diabetic Foot Ulcers: Plain but Not Simple

Hypoxia-inducible factor-1 alpha (HIF-1α) is usually regarded as a core regulator of hypoxic response. Persistent inflammation and impaired wound healing are common manifestations of diabetic foot ulcer (DFU). In normal wounds, HIF-1α and its related regulatory molecules, such as vascular endothelial growth factor and inducible nitric oxide synthase, are activated by hypoxia signals, which in turn promote wound healing. However, abnormal regulation of the HIF-1α signaling pathway by hyperglycemia leads to impaired wound healing in DFU. In this review, we highlight the tissue-specific and stage-specific effects of the HIF-1α signaling pathway in DFU. In the early stage of DFU, HIF-1α in inflammatory cells is over-upregulated by hyperglycemia, causing the activation of nuclear factor-κB and the inducible nitric oxide synthase-mediated pro-inflammatory signaling pathway, leading to sustained inflammation, which is deleterious. In the late stage of DFU, HIF-1α in endothelial cells and keratinocytes is inhibited by hyperglycemia, which leads to the downregulation of vascular endothelial growth factor expression, resulting in insufficient angiogenesis and difficult healing at the wound site. In this review, we discuss recent advances in the knowledge of the HIF-1α signaling pathway and the key targeted molecules in impaired wound healing of DFU. We also summarize the drugs currently in clinical trials that target HIF-1α or its downstream molecules, recapitulate current gaps in our knowledge, and propose rational therapeutic strategies for DFU based on the action characteristics of HIF-1α.