2. Academic Validation
  3. 20-HETE Participates in Intracerebral Hemorrhage-Induced Acute Injury by Promoting Cell Ferroptosis

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

  • Front Neurol. 2021 Nov 12:12:763419. doi: 10.3389/fneur.2021.763419.
Ranran Han 1,  Jieru Wan 1,  Xiaoning Han 1,  Honglei Ren 1,  John R Falck 2,  Sailu Munnuri 2,  Zeng-Jin Yang 1,  Raymond C Koehler 1
Affiliations

Affiliations

  • 1 Department of Anesthesiology and Critical Care Medicine, The Johns Hopkins University, Baltimore, MD, United States.
  • 2 Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX, United States.
PMID: 34867747 DOI: 10.3389/fneur.2021.763419
Abstract

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.

Keywords

20-hydroxyeicosatetraenoic acid; ferroptosis; glutathione peroxidase; intracerebral hemorrhage; lipid peroxide.

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