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

licenses/by-nc-nd/3.0/). Reproduction is permitted for personal, noncommercial use, provided that the article is in whole, unmodified, and properly cited. Received: 2012.11.30; Accepted: 2013.07.23; Published: 2013.08.22 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 some-times 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 b