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Review
. 2021 Dec 13:12:801985.
doi: 10.3389/fimmu.2021.801985. eCollection 2021.

Biological Functions and Regulatory Mechanisms of Hypoxia-Inducible Factor-1α in Ischemic Stroke

Qianyan He  1 , Yinzhong Ma  2 , Jie Liu  1 , Dianhui Zhang  1 , Jiaxin Ren  1 , Ruoyu Zhao  1 , JunLei Chang  2 , Zhen-Ni Guo  1 , Yi Yang  1
Affiliations
Review

Biological Functions and Regulatory Mechanisms of Hypoxia-Inducible Factor-1α in Ischemic Stroke

Qianyan He et al. Front Immunol. .

Abstract

Ischemic stroke is caused by insufficient cerebrovascular blood and oxygen supply. It is a major contributor to death or disability worldwide and has become a heavy societal and clinical burden. To date, effective treatments for ischemic stroke are limited, and innovative therapeutic methods are urgently needed. Hypoxia inducible factor-1α (HIF-1α) is a sensitive regulator of oxygen homeostasis, and its expression is rapidly induced after hypoxia/ischemia. It plays an extensive role in the pathophysiology of stroke, including neuronal survival, neuroinflammation, angiogenesis, glucose metabolism, and blood brain barrier regulation. In addition, the spatiotemporal expression profile of HIF-1α in the brain shifts with the progression of ischemic stroke; this has led to contradictory findings regarding its function in previous studies. Therefore, unveiling the Janus face of HIF-1α and its target genes in different type of cells and exploring the role of HIF-1α in inflammatory responses after ischemia is of great importance for revealing the pathogenesis and identifying new therapeutic targets for ischemic stroke. Herein, we provide a succinct overview of the current approaches targeting HIF-1α and summarize novel findings concerning HIF-1α regulation in different types of cells within neurovascular units, including neurons, endothelial cells, astrocytes, and microglia, during the different stages of ischemic stroke. The current representative translational approaches focused on neuroprotection by targeting HIF-1α are also discussed.

Keywords: HIF-1α; hypoxia; ischemic stroke; neuroinflammation; neuroprotection; neurovascular unit.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
Domain structure of HIF-1α. HIF-1α is comprised of several conserved domains including a DNA binding (basic helix-loop-helix, bHLH) domain, protein/protein interactions and dimerization (PAS) domain, C-terminal trans-activation domain (C-TAD), N-terminal trans-activation domain (N-TAD), oxygen-dependent degradation domain (ODDD), and inhibitory domain (ID).
Figure 2
Figure 2
Regulation of HIF-1α during normoxia and hypoxia. Under normoxia, HIF-1α hydroxylase (PHD) hydroxylates the proline in the presence of iron (Fe2+), which recruits the von Hippel-Lindau protein (pVHL) to bind and initiate the proteolysis of HIF-1α by acting as a recognition component of ubiquitin ligase complex, leading to proteasomal degradation. Under hypoxia conditions, the interaction of transcriptional coactivators p300/CBP (CREB-binding protein) is activated. HIF-1α is stabilized and translocated into the nucleus and heterodimerizes with constitutively expressed HIF-1β, binds to the hypoxia responsive elements (HRE) and enhances the transcription of HIF-1α target genes.
Figure 3
Figure 3
The various physiological functions of HIF-1α and its target genes in different types of cells in the neurovascular unit including neurons, endothelial cells, astrocytes, and microglial cells during ischemic stroke. HIF-1α, hypoxia inducible factor-1α; VEGF, vascular endothelial growth factor; BBB, blood brain barrier; EPO, erythropoietin; GLUT1, glucose transporter 1; ATP, adenosine-triphosphate; ADP, adenosine-diphosphate; IL-4, interleukin-4; IL-10, interleikin-10; TNF-α, tumor necrosis factor-α; IL-6, interleukin-6; TLR4, toll-like receptor 4; NLRP3, recombinant NLR Family, pyrin domain containing protein 3.
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