Disturbed hypoxic responses as a pathogenic mechanism of diabetic foot ulcers

Abstract

Diabetic foot ulceration (DFU) is a chronic complication of diabetes that is characterized by impaired wound healing in the lower extremities. DFU remains a major clinical challenge because of poor understanding of its pathogenic mechanisms. Impaired wound healing in diabetes is characterized by decreased angiogenesis, reduced bone marrow-derived endothelial progenitor cell (EPC) recruitment, and decreased fibroblast and keratinocyte proliferation and migration. Recently, increasing evidence has suggested that increased hypoxic conditions and impaired cellular responses to hypoxia are essential pathogenic factors of delayed wound healing in DFU. Hypoxia-inducible factor-1 (HIF-1, a heterodimer of HIF-1α and HIF-1β) is a master regulator of oxygen homeostasis that mediates the adaptive cellular responses to hypoxia by regulating the expression of genes involved in angiogenesis, metabolic changes, proliferation, migration, and cell survival. However, HIF-1 signalling is inhibited in diabetes as a result of hyperglycaemia-induced HIF-1α destabilization and functional repression. Increasing HIF-1α expression and activity using various approaches promotes angiogenesis, EPC recruitment, and granulation, thereby improving wound healing in experimental diabetes. The mechanisms underlying HIF-1α regulation in diabetes and the therapeutic strategies targeting HIF-1 signalling for the treatment of diabetic wounds are discussed in this review. Further investigations of the pathways involved in HIF-1α regulation in diabetes are required to advance our understanding of the mechanisms underlying impaired wound healing in diabetes and to provide a foundation for developing novel therapeutic approaches to treat DFU.

Effect of Thymoquinone on Wound Healing in Alloxan-Induced Diabetic Rats

“…It is worth noting that impaired wound healing in diabetes is not only just characterized by a decrease in angiogenic function but also in reduction of endothelial progenitor cell recruitment [5]. Saito et al had discovered that the subsets of endothelial progenitors are altered in diabetic rats, resulting in impaired endothelial vascular differentiation [34].…”

“…Ulceration is as a result of collective tissue breakdown manifested by impaired healing [4,5]. This is primarily associated with a series of macrovascular and microvascular alteration that leads to many systemic complications [4,6].…”

Genetic and molecular basis of diabetic foot ulcers: Clinical review

“…combination of intrinsic and extrinsic factors, which include neuropathy, vascular risk factors, wound infection, callus formation and excessive localised pressure (28).…”

“…Wound healing of DFUs are impaired as diabetes involves several complex pathophysiological mechanisms. One of the major hindering components is that DFUs are always accompanied by tissue hypoxia (28,68). Prolonged hypoxia is usually the result of decreased tissue perfusion and inadequate angiogenesis which is unfavourable for the wound healing process.…”

Hyperglycemia-associated alterations in cellular signaling and dysregulated mitochondrial bioenergetics in human metabolic disorders

“…We have recently provided critical discussion on the significance of early hypoxic events on long-term alteration of normative mitochondrial processes in relation to the emergence of pathological states [27, 28, 36–38]. As an example, careful examination of the pathogenicity of diabetic foot ulceration, characterized by poor wound healing, will yield mechanistic links between hypoxic and hyperglycemic conditions and chronic mitochondrial dysfunction [39]. In this regard, increased hypoxic conditions leading to impaired wound healing in diabetic foot ulcerations are functionally associated with impaired hypoxia-inducible factor-1 (HIF-1) expression, an established key regulatory factor in cellular O 2 homeostasis that mediates the adaptive cellular responses to hypoxic challenges.…”