20-HETE Participates in Intracerebral Hemorrhage-Induced Acute Injury by Promoting Cell Ferroptosis

Intracerebral hemorrhage (ICH) is a highly fatal type of stroke that leads to various types of neuronal death. Recently, ferroptosis, a form of cell death resulting from iron-dependent lipid peroxide accumulation, was observed in a mouse ICH model. N-hydroxy-N′-(4-n-butyl-2-methylphenyl)-formamidine...

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Autores principales:	Ranran Han, Jieru Wan, Xiaoning Han, Honglei Ren, John R. Falck, Sailu Munnuri, Zeng-Jin Yang, Raymond C. Koehler
Formato:	article
Lenguaje:	EN
Publicado:	Frontiers Media S.A. 2021
Materias:	20-hydroxyeicosatetraenoic acid intracerebral hemorrhage ferroptosis glutathione peroxidase lipid peroxide Neurology. Diseases of the nervous system RC346-429
Acceso en línea:	https://doaj.org/article/55de5826e0c9473c9899c4cdf2c5f2fe
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spelling	oai:doaj.org-article:55de5826e0c9473c9899c4cdf2c5f2fe2021-11-12T05:32:00Z20-HETE Participates in Intracerebral Hemorrhage-Induced Acute Injury by Promoting Cell Ferroptosis1664-229510.3389/fneur.2021.763419https://doaj.org/article/55de5826e0c9473c9899c4cdf2c5f2fe2021-11-01T00:00:00Zhttps://www.frontiersin.org/articles/10.3389/fneur.2021.763419/fullhttps://doaj.org/toc/1664-2295Intracerebral hemorrhage (ICH) is a highly fatal type of stroke that leads to various types of neuronal death. Recently, ferroptosis, a form of cell death resulting from iron-dependent lipid peroxide accumulation, was observed in a mouse ICH model. N-hydroxy-N′-(4-n-butyl-2-methylphenyl)-formamidine (HET0016), which inhibits synthesis of the arachidonic acid metabolite 20-hydroxyeicosatetraenoic acid (20-HETE), has shown a protective effect after ICH. However, the underlying mechanisms of the neuroprotective effect need further investigation. We explored whether 20-HETE participates in ICH-induced ferroptosis ex vivo by using hemoglobin-treated organotypic hippocampal slice cultures (OHSCs) and in vivo by using a collagenase-induced ICH mouse model. Ex vivo, we found that the 20-HETE synthesis inhibitor HET0016 and antagonist 20-6,15-HEDGE reduced hemoglobin-induced cell death, iron deposition, and lipid reactive oxygen species levels in OHSCs. Furthermore, 20-HETE inhibition in OHSCs increased the expression of glutathione peroxidase (GPX) 4, an antioxidant enzyme that serves as a main regulator of ferroptosis. In contrast, exposure of OHSCs to the 20-HETE stable mimetic 20-5,14-HEDGE induced cell death that was significantly inhibited by the ferroptosis inhibitor ferrostatin-1. In vivo, HET0016 treatment ameliorated focal deficits, reduced lesion volume, and decreased iron accumulation around the lesion at day 3 and 7 after ICH. In addition, lipid peroxidation was decreased and expression of GPX4 was increased in the HET0016-treated ICH group. The mitogen-activated protein kinase pathway also was inhibited by HET0016 in vivo. These results indicate that 20-HETE contributes to ICH-induced acute brain injury in part by activating ferroptosis pathways, thereby providing an upstream target for inhibiting ferroptosis.Ranran HanJieru WanXiaoning HanHonglei RenJohn R. FalckSailu MunnuriZeng-Jin YangRaymond C. KoehlerFrontiers Media S.A.article20-hydroxyeicosatetraenoic acidintracerebral hemorrhageferroptosisglutathione peroxidaselipid peroxideNeurology. Diseases of the nervous systemRC346-429ENFrontiers in Neurology, Vol 12 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	20-hydroxyeicosatetraenoic acid intracerebral hemorrhage ferroptosis glutathione peroxidase lipid peroxide Neurology. Diseases of the nervous system RC346-429
spellingShingle	20-hydroxyeicosatetraenoic acid intracerebral hemorrhage ferroptosis glutathione peroxidase lipid peroxide Neurology. Diseases of the nervous system RC346-429 Ranran Han Jieru Wan Xiaoning Han Honglei Ren John R. Falck Sailu Munnuri Zeng-Jin Yang Raymond C. Koehler 20-HETE Participates in Intracerebral Hemorrhage-Induced Acute Injury by Promoting Cell Ferroptosis
description	Intracerebral hemorrhage (ICH) is a highly fatal type of stroke that leads to various types of neuronal death. Recently, ferroptosis, a form of cell death resulting from iron-dependent lipid peroxide accumulation, was observed in a mouse ICH model. N-hydroxy-N′-(4-n-butyl-2-methylphenyl)-formamidine (HET0016), which inhibits synthesis of the arachidonic acid metabolite 20-hydroxyeicosatetraenoic acid (20-HETE), has shown a protective effect after ICH. However, the underlying mechanisms of the neuroprotective effect need further investigation. We explored whether 20-HETE participates in ICH-induced ferroptosis ex vivo by using hemoglobin-treated organotypic hippocampal slice cultures (OHSCs) and in vivo by using a collagenase-induced ICH mouse model. Ex vivo, we found that the 20-HETE synthesis inhibitor HET0016 and antagonist 20-6,15-HEDGE reduced hemoglobin-induced cell death, iron deposition, and lipid reactive oxygen species levels in OHSCs. Furthermore, 20-HETE inhibition in OHSCs increased the expression of glutathione peroxidase (GPX) 4, an antioxidant enzyme that serves as a main regulator of ferroptosis. In contrast, exposure of OHSCs to the 20-HETE stable mimetic 20-5,14-HEDGE induced cell death that was significantly inhibited by the ferroptosis inhibitor ferrostatin-1. In vivo, HET0016 treatment ameliorated focal deficits, reduced lesion volume, and decreased iron accumulation around the lesion at day 3 and 7 after ICH. In addition, lipid peroxidation was decreased and expression of GPX4 was increased in the HET0016-treated ICH group. The mitogen-activated protein kinase pathway also was inhibited by HET0016 in vivo. These results indicate that 20-HETE contributes to ICH-induced acute brain injury in part by activating ferroptosis pathways, thereby providing an upstream target for inhibiting ferroptosis.
format	article
author	Ranran Han Jieru Wan Xiaoning Han Honglei Ren John R. Falck Sailu Munnuri Zeng-Jin Yang Raymond C. Koehler
author_facet	Ranran Han Jieru Wan Xiaoning Han Honglei Ren John R. Falck Sailu Munnuri Zeng-Jin Yang Raymond C. Koehler
author_sort	Ranran Han
title	20-HETE Participates in Intracerebral Hemorrhage-Induced Acute Injury by Promoting Cell Ferroptosis
title_short	20-HETE Participates in Intracerebral Hemorrhage-Induced Acute Injury by Promoting Cell Ferroptosis
title_full	20-HETE Participates in Intracerebral Hemorrhage-Induced Acute Injury by Promoting Cell Ferroptosis
title_fullStr	20-HETE Participates in Intracerebral Hemorrhage-Induced Acute Injury by Promoting Cell Ferroptosis
title_full_unstemmed	20-HETE Participates in Intracerebral Hemorrhage-Induced Acute Injury by Promoting Cell Ferroptosis
title_sort	20-hete participates in intracerebral hemorrhage-induced acute injury by promoting cell ferroptosis
publisher	Frontiers Media S.A.
publishDate	2021
url	https://doaj.org/article/55de5826e0c9473c9899c4cdf2c5f2fe
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20-HETE Participates in Intracerebral Hemorrhage-Induced Acute Injury by Promoting Cell Ferroptosis

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