Hypoxia-Inducible Factor-1α Target Genes Contribute to Retinal Neuroprotection

Abstract

Hypoxia-inducible factor (HIF) is a transcription factor that facilitates cellular adaptation to hypoxia and ischemia. Long-standing evidence suggests that one isotype of HIF, HIF-1α, is involved in the pathogenesis of various solid tumors and cardiac diseases. However, the role of HIF-1α in retina remains poorly understood. HIF-1α has been recognized as neuroprotective in cerebral ischemia in the past two decades. Additionally, an increasing number of studies has shown that HIF-1α and its target genes contribute to retinal neuroprotection. This review will focus on recent advances in the studies of HIF-1α and its target genes that contribute to retinal neuroprotection. A thorough understanding of the function of HIF-1α and its target genes may lead to identification of novel therapeutic targets for treating degenerative retinal diseases including glaucoma, age-related macular degeneration, diabetic retinopathy, and retinal vein occlusions.

Keywords: HIF-1α; hypoxia preconditioning; neuroprotection; retina; retinal degeneration.

Figure 1

Three-dimensional structures of HIF's alpha subunits and HIF-1α expression levels in normal human nervous tissues. (A) Schematic representation of the crystal structures of HIF-1α, HIF-2α, and HIF-3α proteins reported at the Protein Data Bank (PDB) with PDB ID 4H6J, 4GHI, and 4WN5, respectively (http://www.rcsb.org/pdb/home/home.do). Different structural parts are highlighted in the following colors: magenta: α-helix; yellow: residue in isolated β-bridge; blue: loop; cyan: hydrogen bounded turn; white: bend. They contain the N-terminus, central region and C-terminus. (B) HIF-1α mRNA expression levels in normal human nervous tissues (normalized intensities in microarray) reported in Genecards (http://www.genecards.org).

Figure 2

Pathways of HIF-1α and its target genes involved in retinal neuroprotection. The upper panel in yellow background is the schematic representation of HIF-1α degradation under normoxia. Note that the undegraded HIF-1α binds with HIF-1β to form the HIF-1α/β complex. The complex binds to HIF-responsive elements (HREs) in promoters that contain the sequence motif 5′-NCGTG-3′ and triggers transcription of more than 100 downstream genes. VHL: von Hippel–Lindau tumor suppressor protein (E3 ubiquitin protein ligase). The lower panel in pale blue color represents the HIF-1α target genes and their acting pathways involved in retinal neuroprotection under hypoxia. Note that five main cellular signaling pathways mediating the effect of neuroprotection are highlighted. Firstly, EPO binds to EPO-R to promote ERK-1/2 signaling, and then activate the Akt pathway, resulting in cell proliferation, anti-apoptosis, anti-inflammation, and angiogenesis. Also, it can maintain mitochondrial membrane potential to prevent mitochondrial alteration. In particular, EPO can be pumped outside the cytoplasm, which leads to the autocrine and paracrine effects that further exert retinal neuroprotection. Secondly, VEGF, which binds to VEGF-R, can achieve the same effects as EPO through activating ERK-1/2 signaling. Simultaneously, it enhances the MEK-1/2 pathway, promoting angiogenesis and inhibiting caspase-3 to constrain cell death. Thirdly, the secreted multifunctional peptide ADM mainly plays roles in vasomotor regulation, and acts together with VEGF to promote angiogenesis. Fourthly, Glut-1 transports glucose to the cytoplasm, allowing normal metabolic activity. Fifthly, HO-1 is degraded by ARE/EpRE elements. While under hypoxia, HO-1 blunts reactive oxygen species (ROS) production and the toxic effect on mitochondria. More importantly, HO-1 retards retinal injury through the IRS1/PI3K/Akt2 and Keap1/Nrf2 pathways, which further activate mTOR, upregulate anti-apoptotic proteins, and eliminate ROS.