The Possible Mechanisms Underlying the Impairment of HIF-1α Pathway Signaling in Hyperglycemia and the Beneficial Effects of Certain Therapies

Abstract

Hypoxia-inducible factor 1 alpha (HIF-1α), an essential transcription factor which mediates the adaptation of cells to low oxygen tensions, is regulated precisely by hypoxia and hyperglycemia, which are major determinants of the chronic complications associated with diabetes. The process of HIF-1α stabilization by hypoxia is clear; however, the mechanisms underlying the potential deleterious effect of hyperglycemia on HIF-1α are still controversial, despite reports of a variety of studies demonstrating the existence of this phenomenon. In fact, HIF-1α and glucose can sometimes influence each other: HIF-1α induces the expression of glycolytic enzymes and glucose metabolism affects HIF-1α accumulation in some cells. Although hyperglycemia upregulates HIF-1α signaling in some specific cell types, we emphasize the inhibition of HIF-1α by high glucose in this review. With regard to the mechanisms of HIF-1α impairment, the role of methylglyoxal in impairment of HIF-1α stabilization and transactivation ability and the negative effect of reactive oxygen species (ROS) on HIF-1α are discussed. Other explanations for the inhibition of HIF-1α by high glucose exist: the increased sensitivity of HIF-1α to Von Hippel-Lindau (VHL) machinery, the role of osmolarity and proteasome activity, and the participation of several molecules. This review aims to summarize several important developments regarding these mechanisms and to discuss potentially effective therapeutic techniques (antioxidants eicosapentaenoic acid (EPA) and metallothioneins (MTs), pharmaceuticals cobalt chloride (CoCl2), dimethyloxalylglycine (DMOG), desferrioxamine (DFO) and gene transfer of constitutively active forms of HIF-1α) and their mechanisms of action for intervention in the chronic complications in diabetes.

Intermittent hypoxia training in prediabetes patients: Beneficial effects on glucose homeostasis, hypoxia tolerance and gene expression

“…11,17,20,21,54 Reduced levels of HIF-1a have been found in the cells or tissues collected from diabetic animals or patients, indicating an inhibitory effect of hyperglycemia on HIF-1a expression. 18,[55][56][57][58][59] This diabetes-blunted HIF-1a response to hypoxic conditions may result in impaired angiogenesis and inability to upregulate glycolytic ATP generation in the type 2 diabetic heart. 60 The selection of leukocytes to be studied on cellular response to hypoxia had several rationales.…”

Knockdown of hypoxia inducible factor-2α inhibits cell invasion via the downregulation of MMP-2 expression in breast cancer cells

“…CoCl 2 prevents HIF-1α from binding to prolyl hydroxylases, so that they are not hydroxylated and are subsequently degraded by proteasomes (31). CoCl 2 has been used in in vivo and in vitro studies to generate hypoxia by inhibiting HIF-1 specific prolyl-hydroxylase and occupying its iron-binding site, leading to impaired binding of the von Hippel-Lindau protein with HIF-1α, subsequently preventing HIF-1α proteasomal degradation (32).…”

Upregulation of HSP70 Extends Cytoprotection to Fish Brain under Xenobiotic Stress

“…Hypoxia-inducible factors (HIF's) are regulatory proteins consisting of two subunits namely HIF-1α and HIF-1β that display different responses to O 2 concentrations: HIF-1β is a non-oxygen-responsive nuclear protein and is constitutively expressed; HIF-1α is an essential transcription factor which mediates the adaptation of cells to low oxygen tensions, is regulated precisely by hypoxia (Xiao et al 2013). During normoxia HIF-1α is synthesized at a high rate, but is degraded immediately.…”