The Role of Hypoxia-Inducible Factor 1 in Mild Cognitive Impairment

Iyalomhe, Osigbemhe; Świerczek, Sabina; Enwerem, Ngozi; Chen, Yuanxiu; Adedeji, Monica O.; Allard, Joanne; Ntekim, Oyonumo; Johnson, Stephen E.; Hughes, Kakra; Kurian, Philip; Obisesan, Thomas O.

doi:10.1007/s10571-016-0440-6

Cited by 50 publications

(40 citation statements)

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“…The induction of hypoxiasignaling pathways (e.g., HIF-1 stabilization) has been proposed as a therapeutic target for mitigating or preventing neurodegenerative diseases such as cerebral ischemic stroke, Alzheimer's disease, Parkinson's disease, Huntington's disease, and prion-related diseases (59)(60)(61)(62)(63). HIF-1 triggers the expression of several genes involved in angiogenesis, oxygen transport, glycolytic metabolism, cell survival, apoptosis, and other processes that diminish neural cell death, increase cerebral blood flow, stimulate neurorepair process, and mitigate cognitive deterioration (59)(60)(61)(62)(63)(64)(65).…”

Section: Discussionmentioning

confidence: 99%

HIF‐1α stabilization reduces retinal degeneration in a mouse model of retinitis pigmentosa

et al. 2018

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Retinitis pigmentosa (RP) is a group of inherited retinal dystrophies characterized by progressive and irreversible loss of vision due to rod and cone degeneration. Evidence suggests that an inappropriate oxygen level could contribute to its pathogenesis. Rod cell death could increase oxygen concentration, reduce hypoxia-inducible factor 1 (HIF-1α) and contribute to cone cell death. The purposes of this study were: 1) to analyze the temporal profile of HIF-1α, its downstream effectors VEGF, endothelin-1 (ET-1), iNOS, and glucose transporter 1 (GLUT1), and neuroinflammation in retinas of the murine model of rd10 ( retinal degeneration 10) mice with RP; 2) to study oxygen bioavailability in these retinas; and 3) to investigate how stabilizing HIF-1α proteins with dimethyloxaloglycine (DMOG), a prolyl hydroxylase inhibitor, affects retinal degeneration, neuroinflammation, and antioxidant response in rd10 mice. A generalized down-regulation of HIF-1α and its downstream targets was detected in parallel with reactive gliosis, suggesting high oxygen levels during retinal degeneration. At postnatal d 18, DMOG treatment reduced photoreceptor cell death and glial activation. In summary, retinas of rd10 mice seem to be exposed to a hyperoxic environment even at early stages of degeneration. HIF-1α stabilization could have a temporal neuroprotective effect on photoreceptor cell survival, glial activation, and antioxidant response at early stages of RP.-Olivares-González, L., Martínez-Fernández de la Cámara, C., Hervás, D., Millán, J. M., Rodrigo, R. HIF-1α stabilization reduces retinal degeneration in a mouse model of retinitis pigmentosa.

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Section: Discussionmentioning

confidence: 99%

HIF‐1α stabilization reduces retinal degeneration in a mouse model of retinitis pigmentosa

et al. 2018

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“…Despite the fact that HIF regulation has primarily been thought oxygen concentration, several studies have showed that HIF-1α can have an oxygen-independent regulation, such as in response to hyperglycemia, oxidative stress, and inflammatory proteins ( Cramer et al, 2003 ; Catrina, 2014 ; Corcoran and O’Neill, 2016 ). Hypoxia is an important factor in the pathophysiology of a number of human diseases (e.g., obesity, insulin resistance, diabetes, Alzheimer disease, and aging) that are characterized by the presence of inflammatory processes ( Eltzschig and Carmeliet, 2011 ; Iyalomhe et al, 2017 ). Hypoxia can also lead to the production of oxygen radicals, which, as well, have important implications in these diseases.…”

Section: Hif Canonical Pathway and Cellular Functionsmentioning

confidence: 99%

Hypoxia Inducible Factor as a Central Regulator of Metabolism – Implications for the Development of Obesity

Gaspar

Velloso

2018

Front. Neurosci.

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The hypothalamus plays a major role in the regulation of food intake and energy expenditure. In the last decade, it was demonstrated that consumption of high-fat diets triggers the activation of an inflammatory process in the hypothalamus, inducing neurofunctional alterations and contributing to the development of obesity. Hypoxia-inducible factors (HIFs) are key molecules that regulate cellular responses to inflammation and hypoxia, being essential for the normal cell function and survival. Currently, evidence points to a role of HIF pathway in metabolic regulation that could also be involved in the progression of obesity and metabolic diseases. The challenge is to understand how HIF modulation impacts body mass gain and metabolic disorders such as insulin resistance. Distinct animal models with tissue-specific knocking-out or overexpression of hypoxia signaling pathway genes revealed a cell-specificity in the activation of HIF pathways, and some of them have opposite phenotypes among the various HIFs gain- and loss-of-function mouse models. In this review, we discuss the major findings that provide support for a role of HIF pathway involvement in the regulation of metabolism, especially in glucose and energy homeostasis.

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“…Increased HIF-1a expression and activity have been shown to promote glycolysis and glucose metabolism, thus countering oxidative stress by producing NADH and NADPH to propagate neuroprotective responses (Soucek et al 2003). HIF-1a has also been shown to improve cerebral blood flow, which could oppose the toxicity of hypoxia (Iyalomhe et al 2017). Overexpression of HIF-1a and/or HIF-1a target genes, such as VEGF-A and EPO, may be an early adaptation to the oxidative stressors that characterize MeHginduced neuropathology.…”

Section: Introductionmentioning

confidence: 99%

Acute Methylmercury Exposure and the Hypoxia-Inducible Factor-1α Signaling Pathway under Normoxic Conditions in the Rat Brain and Astrocytes in Vitro

Chang

Yang

Zhou

et al. 2019

Environ Health Perspect

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BACKGROUND: As a ubiquitous environmental pollutant, methylmercury (MeHg) induces toxic effects in the nervous system, one of its main targets. However, the exact mechanisms of its neurotoxicity have not been fully elucidated. Hypoxia-inducible factor-1a (HIF-1a), a transcription factor, plays a crucial role in adaptive and cytoprotective responses in cells and is involved in cell survival, proliferation, apoptosis, inflammation, angiogenesis, glucose metabolism, erythropoiesis, and other physiological activities. OBJECTIVES: The aim of this study was to explore the role of HIF-1a in response to acute MeHg exposure in rat brain and primary cultured astrocytes to improve understanding of the mechanisms of MeHg-induced neurotoxicity and the development of effective neuroprotective strategies. METHODS: Primary rat astrocytes were treated with MeHg (0-10 lM) for 0:5 h. Cell proliferation and cytotoxicity were assessed with a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl diphenyltetrazolium bromide (MTT) assay and a lactate dehydrogenase (LDH) release assay, respectively. Reactive oxygen species (ROS) levels were analyzed to assess the level of oxidative stress using 2 0 ,7 0-dichlorofluorescin diacetate (DCFH-DA) fluorescence. HIF-1a, and its downstream proteins, glucose transporter 1 (GLUT-1), erythropoietin (EPO), and vascular endothelial growth factor A (VEGF-A) were analyzed by means of Western blotting. Real-time PCR was used to detect the expression of HIF-1a mRNA. Pretreatment with protein synthesis inhibitor (CHX), proteasome inhibitor (MG132), or proline hydroxylase inhibitor (DHB) were applied to explore the possible mechanisms of HIF-1a inhibition by MeHg. To investigate the role of HIF-1a in MeHg-induced neurotoxicity, cobalt chloride (CoCl 2), 2-methoxyestradiol (2-MeOE2), small interfering RNA (siRNA) transfection and adenovirus overexpression were used. Pretreatment with N-acetyl-L-cysteine (NAC) and vitamin E (Trolox) were used to investigate the putative role of oxidative stress in MeHg-induced alterations in HIF-1a levels. The expression of HIF-1a and related downstream proteins was detected in adult rat brain exposed to MeHg (0-10 mg=kg) for 0:5 h in vivo. RESULTS: MeHg caused lower cell proliferation and higher cytotoxicity in primary rat astrocytes in a time-and concentration-dependent manner. In comparison with the control cells, exposure to 10 lM MeHg for 0:5 h significantly inhibited the expression of astrocytic HIF-1a, and the downstream genes GLUT-1, EPO, and VEGF-A (p < 0:05), in the absence of a significant decrease in HIF-1a mRNA levels. When protein synthesis was inhibited by CHX, MeHg promoted the degradation rate of HIF-1a. MG132 and DHB significantly blocked the MeHg-induced decrease in HIF-1a expression (p < 0:05). Overexpression of HIF-1a significantly attenuated the decline in MeHg-induced cell proliferation, whereas the inhibition of HIF-1a significantly increased the decline in cell proliferation (p < 0:05). NAC and Trolox, two established antioxidants, reversed the MeHg-induced decl...

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The Role of Hypoxia-Inducible Factor 1 in Mild Cognitive Impairment

Cited by 50 publications

References 100 publications

HIF‐1α stabilization reduces retinal degeneration in a mouse model of retinitis pigmentosa

HIF‐1α stabilization reduces retinal degeneration in a mouse model of retinitis pigmentosa

Hypoxia Inducible Factor as a Central Regulator of Metabolism – Implications for the Development of Obesity

Acute Methylmercury Exposure and the Hypoxia-Inducible Factor-1α Signaling Pathway under Normoxic Conditions in the Rat Brain and Astrocytes in Vitro

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