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.

Keywords: Hyperglycemia; Hypoxia-inducible factor 1 alpha (HIF-1α); Methylglyoxal (MGO); Prolyl hydroxylases (PHDs); Reactive oxidative species (ROS); Therapy..

Fig 1

Possible mechanisms underlying the impairment of the HIF-1α pathway by hyperglycemia (1). A, B, C, D: the effects of MGO on HIF-1α; A: The covalent modification of HIF-1α leads to decreased dimerization of HIF-1α and HIF-1β, and further reduces the binding of HIF-1 and HRE; B: The covalent modification of p300 leads to inhibition of the interaction of CTAD and p300, which decreases the transactivation ability of HIF-1α; C: The covalent modification of HIF-1α increases its association with HSP40/70, which recruits CHIP and leads to HIF-1α proteasomal degradation; D: The exposure of RPE cells to MGO leads to destabilization of HIF-1α; E: Hyperglycemia increases the sensitivity of hydroxyl HIF-1α to VHL machinery; F: Hyperglycemia suppresses CTAD and NTAD, and finally reduces the transactivation ability of HIF-1α; G: In HDF and HDMEC, osmolarity is one of the mechanisms of hyperglycemia action; H: The impairment of HIF-1α stabilization by hyperglycemia is mediated by proteasomal degradation. CBP: CREB binding protein; CHIP: carboxyl terminus of the Hsc70-interacting protein; CREB: cAMP-response element binding protein; CTAD: carboxy-terminal transactivation domain; HDF: human dermal fibroblast; HDMEC: human dermal microvascular endothelial cells; HIF-1: hypoxia-inducible factor 1; HREs: hypoxia response elements; Hsc70: heat-shock cognate protein 70; Hsp40/70: heat shock protein 40/70; MGO: methylglyoxal; NTAD: amino-terminal transactivation domain; OH: hydroxy; PHDs: prolyl hydroxylases; RPE: retinal pigment epithelial cells; Ub: ubiquitin; VHL: Von Hippel-Lindau protein.

Fig 2

Possible mechanisms underlying the impairment of the HIF-1α pathway by hyperglycemia (2). A, B, C: the roles of hyperglycemia-induced ROS; A: The reaction between O₂^- and NO results in a decrease in steady-state NO concentration and thereby reduces NO-induced HIF-1α accumulation and activation; B: Rac1 contributes to HIF-1α expression and transactivation; ROS inhibits HIF-1 expression through repression of Rac1 expression; C: ROS degrade HIF-1α by activating a proline hydroxylase in the presence of iron and by increasing ubiquitin-proteasome activity; D: The inhibition of HIF-1α might be involved in the role of TNF-α, angiotensin II and the insulin pathway (insulin, IGF-1, IGF-2). HIF-1: hypoxia-inducible factor 1; IGF: insulin-like growth factor; NO: nitric oxide; O₂^-: superoxide; PHDs: prolyl hydroxylases; ROS: reactive oxygen species; TNF-α: tumor necrosis factor-α.