title: 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.
authors: Department of Endocrinology, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou 510655, China.
authors: Haijuan
authors: H
authors: Xiao
authors: Zhenyang
authors: Z
authors: Gu
authors: Guoxing
authors: G
authors: Wang
authors: Tongfeng
authors: T
authors: Zhao
mesh_terms: D000818:Animals; D006801:Humans; D006943:Hyperglycemia / Q000235:genetics / Q000378:metabolism*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism*; D064828:Prolyl Hydroxylases / Q000378:metabolism; D011765:Pyruvaldehyde / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D017382:Reactive Oxygen Species; D011765:Pyruvaldehyde; D064828:Prolyl Hydroxylases
keywords: Hyperglycemia; Hypoxia-inducible factor 1 alpha (HIF-1α); Methylglyoxal (MGO); Prolyl hydroxylases (PHDs); Reactive oxidative species (ROS); Therapy.
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