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

Hypoxia-inducible factor 1 alpha (HIF-1 alpha), 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-1 alpha stabilization by hypoxia is clear; however, the mechanisms underlying the potential deleterious effect of hyperglycemia on HIF-1 alpha are still controversial, despite reports of a variety of studies demonstrating the existence of this phenomenon. In fact, HIF-1 alpha and glucose can sometimes influence each other: HIF-1 alpha induces the expression of glycolytic enzymes and glucose metabolism affects HIF-1 alpha accumulation in some cells. Although hyperglycemia upregulates HIF-1 alpha signaling in some specific cell types, we emphasize the inhibition of HIF-1 alpha by high glucose in this review. With regard to the mechanisms of HIF-1 alpha impairment, the role of methylglyoxal in impairment of HIF-1 alpha stabilization and transactivation ability and the negative effect of reactive oxygen species (ROS) on HIF-1 alpha are discussed. Other explanations for the inhibition of HIF-1 alpha by high glucose exist: the increased sensitivity of HIF-1 alpha 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-1 alpha) and their mechanisms of action for intervention in the chronic complications in diabetes.