The role of HIFs in ischemia-reperfusion injury

Neil J Howell, Daniel A Tennant, Neil J Howell, Daniel A Tennant

Abstract

The reduction or cessation of the blood supply to an organ results in tissue ischemia. Ischemia can cause significant tissue damage, and is observed as a result of a thrombosis, as part of a disease process, and during surgery. However, the restoration of the blood supply often causes more damage to the tissue than the ischemic episode itself. Research is therefore focused on identifying the cellular pathways involved in the protection of organs from the damage incurred by this process of ischemia reperfusion (I/R). The hypoxia-inducible factors (HIFs) are a family of heterodimeric transcription factors that are stabilized during ischemia. The genes that are expressed downstream of HIF activity enhance oxygen-independent ATP generation, cell survival, and angiogenesis, amongst other phenotypes. They are, therefore, important factors in the protection of tissues from I/R injury. Interestingly, a number of the mechanisms already known to induce organ protection against I/R injury, including preconditioning, postconditioning, and activation of signaling pathways such as adenosine receptor signaling, converge on the HIF system. This review describes the evidence for HIFs playing a role in I/R protection mediated by these factors, highlights areas that require further study, and discuss whether HIFs themselves are good therapeutic targets for protecting tissues from I/R injury.

Keywords: adenosine; hypoxia; post-conditioning; pre-conditioning.

Figures

Figure 1
Figure 1
The control of HIF expression and activity by factors involved in ischemic signaling. Notes: HIFα expression is directly regulated by oxygen-dependent PHD enzymes that hydroxylate it in two positions for recognition by the pVHL E3 ubiquitin ligase, which targets HIFα for proteasomal degradation. PHD activity can be further controlled by changes in ROS and succinate levels, both of which are increased through mitochondrial dysfunction during ischemia. Further regulation of expression is performed through MAPK- and mTOR-mediated control of mRNA translation. Receptor tyrosine kinase signaling can increase HIF expression and activity through mTOR and MAPK signaling, while both the adenosine receptors 2A/B and cellular stresses can increase HIF activity through MAPK activation. MAPK-mediated phosphorylation of HIF1α is necessary for efficient transactivation of its target genes by enhancing the interaction with p300/CBP. Abbreviations: α-KG, α-ketoglutarate; A2A/B, adenosine receptors 2A/B; ADORA2A, gene encoding A2A receptor; CD73, the membrane-bound extracellular 5′-nucleotidase; ETC, electron transport chain; Gs, stimulatory G protein; HIF, hypoxia-inducible factor; MAPK, mitogen-activated protein kinase; mTOR, mechanistic target of rapamycin; P, phosphorylated peptide residue; p300/CBP, p300/cyclic AMP adenosine monophosphate; PHD, HIF prolyl hydroxylase enzyme; pVHL, von-Hippel Lindau protein; ROS, reactive oxygen species; RTK, receptor tyrosine kinase; TCA, tricarboxylic acid cycle; Ub, ubiquitin; mRNA, messenger RNA.

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