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

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.

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Monocyte Transmodulation: The Next Novel Therapeutic Approach in Overcoming Ischemic Stroke?

Frontiers in Neurology ◽

10.3389/fneur.2020.578003 ◽

2020 ◽

Vol 11 ◽

Author(s):

Joohyun Park ◽

Ji Young Chang ◽

Jong Youl Kim ◽

Jong Eun Lee

Keyword(s):

Ischemic Stroke ◽

Blood Cells ◽

Inflammatory Responses ◽

Peripheral Blood Leukocytes ◽

Blood Leukocytes ◽

Great Opportunity ◽

Reparative Process ◽

The Brain ◽

Vital Element

The immune response following neuroinflammation is a vital element of ischemic stroke pathophysiology. After the onset of ischemic stroke, a specialized vasculature system that effectively protects central nervous system tissues from the invasion of blood cells and other macromolecules is broken down within minutes, thereby triggering the inflammation cascade, including the infiltration of peripheral blood leukocytes. In this series of processes, blood-derived monocytes have a significant effect on the outcome of ischemic stroke through neuroinflammatory responses. As neuroinflammation is a necessary and pivotal component of the reparative process after ischemic stroke, understanding the role of infiltrating monocytes in the modulation of inflammatory responses may offer a great opportunity to explore new therapies for ischemic stroke. In this review, we discuss and highlight the function and involvement of monocytes in the brain after ischemic injury, as well as their impact on tissue damage and repair.

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Hypoxia and HIF Signaling: One Axis with Divergent Effects

International Journal of Molecular Sciences ◽

10.3390/ijms21165611 ◽

2020 ◽

Vol 21 (16) ◽

pp. 5611 ◽

Cited By ~ 2

Author(s):

Chiara Corrado ◽

Simona Fontana

Keyword(s):

Cellular Response ◽

Target Genes ◽

Hypoxia Inducible Factor ◽

Biological Processes ◽

Oxygen Homeostasis ◽

Tissue Responses ◽

Liver And Kidney ◽

Heterodimeric Complex ◽

Complex Activities

The correct concentration of oxygen in all tissues is a hallmark of cellular wellness, and the negative regulation of oxygen homeostasis is able to affect the cells and tissues of the whole organism. The cellular response to hypoxia is characterized by the activation of multiple genes involved in many biological processes. Among them, hypoxia-inducible factor (HIF) represents the master regulator of the hypoxia response. The active heterodimeric complex HIF α/β, binding to hypoxia-responsive elements (HREs), determines the induction of at least 100 target genes to restore tissue homeostasis. A growing body of evidence demonstrates that hypoxia signaling can act by generating contrasting responses in cells and tissues. Here, this dual and controversial role of hypoxia and the HIF signaling pathway is discussed, with particular reference to the effects induced on the complex activities of the immune system and on mechanisms determining cell and tissue responses after an injury in both acute and chronic human diseases related to the heart, lung, liver, and kidney.

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The mMiR-223: An inflammatory MicroRNA Involved in Pathogenesis of Multiple Sclerosis

International Journal of Medical Laboratory ◽

10.18502/ijml.v5i4.152 ◽

2018 ◽

Author(s):

Saba Gharibi ◽

Bahram Moghimi ◽

Mohammad Taher Tahoori ◽

Mohammad Bagher Mahmudi ◽

Ensieh Shahvazian ◽

...

Keyword(s):

Multiple Sclerosis ◽

Target Genes ◽

Demyelinating Disease ◽

Inflammatory Responses ◽

Critical Role ◽

Protein Coding ◽

Mirna Genes ◽

Brain And Spinal Cord ◽

The Brain

Multiple sclerosis (MS) is the most common autoimmune inflammatory demyelinating disease that affects the brain and spinal cord. Dysregulation or mutation of miRNA genes have been linked to the pathogenesis of MS. The miRNAs are short, 20-22 nucleotide long, single-stranded regulatory and non–protein coding RNAs that modulate the expression of multiple target genes. Among miRNAs, miR-223 has been reported to play a critical role in MS. This review concentrates on the emerging role of miR-223 in inflammatory responses and specifically discusses how alterations in miR-223 expression are associated with the development of MS. This review also suggests that miR-223 can be used as a biomarker for diagnosis of MS and discovering novel therapeutics for MS treatment.

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Mesenchymal Stem Cell Derived Extracellular Vesicles for Repairing the Neurovascular Unit after Ischemic Stroke

Cells ◽

10.3390/cells10040767 ◽

2021 ◽

Vol 10 (4) ◽

pp. 767

Author(s):

Courtney Davis ◽

Sean I. Savitz ◽

Nikunj Satani

Keyword(s):

Ischemic Stroke ◽

Extracellular Vesicles ◽

Neurovascular Unit ◽

Culture Conditions ◽

Therapeutic Effects ◽

Stroke Treatment ◽

Inflammatory Molecules ◽

The Brain

Ischemic stroke is a debilitating disease and one of the leading causes of long-term disability. During the early phase after ischemic stroke, the blood-brain barrier (BBB) exhibits increased permeability and disruption, leading to an influx of immune cells and inflammatory molecules that exacerbate the damage to the brain tissue. Mesenchymal stem cells have been investigated as a promising therapy to improve the recovery after ischemic stroke. The therapeutic effects imparted by MSCs are mostly paracrine. Recently, the role of extracellular vesicles released by these MSCs have been studied as possible carriers of information to the brain. This review focuses on the potential of MSC derived EVs to repair the components of the neurovascular unit (NVU) controlling the BBB, in order to promote overall recovery from stroke. Here, we review the techniques for increasing the effectiveness of MSC-based therapeutics, such as improved homing capabilities, bioengineering protein expression, modified culture conditions, and customizing the contents of EVs. Combining multiple techniques targeting NVU repair may provide the basis for improved future stroke treatment paradigms.

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The experimental study of hypoxia-inducible factor-1α and its target genes in spinal cord injury

Spinal Cord ◽

10.1038/sj.sc.3101813 ◽

2005 ◽

Vol 44 (1) ◽

pp. 35-43 ◽

Cited By ~ 31

Author(s):

H Xiaowei ◽

Z Ninghui ◽

X Wei ◽

T Yiping ◽

X Linfeng

Keyword(s):

Spinal Cord ◽

Experimental Study ◽

Spinal Cord Injury ◽

Target Genes ◽

Hypoxia Inducible Factor ◽

Hypoxia Inducible Factor 1Α ◽

Cord Injury

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Nitric Oxide Is a Factor in the Stabilization of Hypoxia-Inducible Factor-1α in Cancer: Role of Free Radical Formation

Cancer Research ◽

10.1158/0008-5472.can-05-0333 ◽

2006 ◽

Vol 66 (2) ◽

pp. 770-774 ◽

Cited By ~ 76

Author(s):

Marisol Quintero ◽

Peter A. Brennan ◽

Gareth J. Thomas ◽

Salvador Moncada

Keyword(s):

Nitric Oxide ◽

Free Radical ◽

Hypoxia Inducible Factor ◽

Radical Formation ◽

Hypoxia Inducible Factor 1Α ◽

Free Radical Formation

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Therapeutically Targeting Neuroinflammation and Microglia after Acute Ischemic Stroke

BioMed Research International ◽

10.1155/2014/297241 ◽

2014 ◽

Vol 2014 ◽

pp. 1-9 ◽

Cited By ~ 40

Author(s):

Youngjeon Lee ◽

Sang-Rae Lee ◽

Sung S. Choi ◽

Hyeon-Gu Yeo ◽

Kyu-Tae Chang ◽

...

Keyword(s):

Ischemic Stroke ◽

Acute Ischemic Stroke ◽

Inflammatory Responses ◽

Secondary Injury ◽

Initial Event ◽

Stroke Models ◽

Anti Inflammatory ◽

Preclinical And Clinical Studies ◽

Multiple Receptor

Inflammation has a pivotal role in the pathogenesis of ischemic stroke, and recent studies posit that inflammation acts as a double-edged sword, not only detrimentally augmenting secondary injury, but also potentially promoting recovery. An initial event of inflammation in ischemic stroke is the activation of microglia, leading to production of both pro- and anti-inflammatory mediators acting through multiple receptor signaling pathways. In this review, we discuss the role of microglial mediators in acute ischemic stroke and elaborate on preclinical and clinical studies focused on microglia in stroke models. Understanding how microglia can lead to both pro- and anti-inflammatory responses may be essential to implement therapeutic strategies using immunomodulatory interventions in ischemic stroke.

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Hypoxia-inducible factor 1α induces osteo/odontoblast differentiation of human dental pulp stem cells via Wnt/β-catenin transcriptional cofactor BCL9

Scientific Reports ◽

10.1038/s41598-021-04453-8 ◽

2022 ◽

Vol 12 (1) ◽

Author(s):

Shion Orikasa ◽

Nobuyuki Kawashima ◽

Kento Tazawa ◽

Kentaro Hashimoto ◽

Keisuke Sunada-Nara ◽

...

Keyword(s):

Stem Cells ◽

Dental Pulp ◽

Target Genes ◽

Hypoxia Inducible Factor ◽

Dental Pulp Stem Cells ◽

Pulp Tissue ◽

Odontoblast Differentiation ◽

Hypoxia Inducible Factor 1Α ◽

Hypoxic Conditions

AbstractAccelerated dental pulp mineralization is a common complication in avulsed/luxated teeth, although the mechanisms underlying this remain unclear. We hypothesized that hypoxia due to vascular severance may induce osteo/odontoblast differentiation of dental pulp stem cells (DPSCs). This study examined the role of B-cell CLL/lymphoma 9 (BCL9), which is downstream of hypoxia-inducible factor 1α (HIF1α) and a Wnt/β-catenin transcriptional cofactor, in the osteo/odontoblastic differentiation of human DPSCs (hDPSCs) under hypoxic conditions. hDPSCs were isolated from extracted healthy wisdom teeth. Hypoxic conditions and HIF1α overexpression induced significant upregulation of mRNAs for osteo/odontoblast markers (RUNX2, ALP, OC), BCL9, and Wnt/β-catenin signaling target genes (AXIN2, TCF1) in hDPSCs. Overexpression and suppression of BCL9 in hDPSCs up- and downregulated, respectively, the mRNAs for AXIN2, TCF1, and the osteo/odontoblast markers. Hypoxic-cultured mouse pulp tissue explants showed the promotion of HIF1α, BCL9, and β-catenin expression and BCL9-β-catenin co-localization. In addition, BCL9 formed a complex with β-catenin in hDPSCs in vitro. This study demonstrated that hypoxia/HIF1α-induced osteo/odontoblast differentiation of hDPSCs was partially dependent on Wnt/β-catenin signaling, where BCL9 acted as a key mediator between HIF1α and Wnt/β-catenin signaling. These findings may reveal part of the mechanisms of dental pulp mineralization after traumatic dental injury.

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Therapeutic effects of Hypoxia-Inducible Factor-1α (HIF-1α) on bone formation around implants in diabetic mice

10.1101/392670 ◽

2018 ◽

Author(s):

Sang-Min Oh ◽

Jin-Su Shin ◽

Il-Koo Kim ◽

Jae-Seung Moon ◽

Jung-Ho Kim ◽

...

Keyword(s):

Bone Formation ◽

Rna Sequencing ◽

Normal Mouse ◽

Target Genes ◽

Hypoxia Inducible Factor ◽

Diabetic Mouse ◽

Differentially Expressed ◽

Diabetic Patients ◽

Diabetic Mice ◽

Hypoxia Inducible Factor 1Α

AbstractPatients with uncontrolled diabetes are susceptible to implant failure due to impaired bone metabolism. Hypoxia-Inducible Factor 1α (HIF-1α), a transcription factor that is up-regulated in response to reduced oxygen condition during the bone repair process after fracture or osteotomy, is known to mediate angiogenesis and osteogenesis. However, its function is inhibited under hyperglycemic conditions in diabetic patients. The aim of this study is to evaluate the effects of exogenous HIF-1α on bone formation around implants by applying HIF-1α to diabetic mice via a novel PTD-mediated DNA delivery system. Smooth surface implants (1mm in diameter; 2mm in length) were placed in the both femurs of diabetic and normal mice. HIF-1α and placebo gels were injected to implant sites of the right and left femurs, respectively: Normal mouse with HIF-1α gel (NH), Normal mouse with placebo gel (NP), Diabetic mouse with HIF-1α gel (DH), and Diabetic mouse with placebo gel (DP). RNA sequencing was performed 4 days after surgery. Based on RNA sequencing, Differentially Expressed Genes (DEGs) were identified and HIF-1α target genes were selected. Histologic and histomorphometric results were evaluated 2 weeks after the surgery. The results showed that bone-to-implant contact (BIC) and bone volume (BV) were significantly greater in the DH group than the DP group (p < 0.05). A total of 216 genes were differentially expressed in DH group compared to DP group. On the other hand, there were 95 DEGs in the case of normal mice. Twenty-one target genes of HIF-1α were identified in diabetic mice through bioinformatic analysis of DEGs. Among the target genes, NOS2, GPNMB, CCL2, CCL5, CXCL16 and TRIM63 were manually found to be associated with wound healing-related genes. In conclusion, local administration of HIF-1α via PTD may help bone formation around the implant and induce gene expression more favorable to bone formation in diabetic mice.

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