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

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.

Dexpramipexole Attenuates White Matter Injury to Facilitate Locomotion and Motor Coordination Recovery via Reducing Ferroptosis after Intracerebral Hemorrhage

“…Here, GPX4 is downregulated with the presence of elevated lipid peroxidation at perihematomal site after ICH, which is consistent with previous studies [43][44][45][46]. Meanwhile, the results also report that GPX4 upregulation induced by the administration of DPX alleviates lipid peroxidation injury to neural cells after ICH, which is in line with previous studies that elevated GPX4 expression mitigates ICH-induced acute brain injury by activating ferroptosis [44,46,47]. To our limited knowledge, it is the first work to provide a rationale that DPX inhibits ferroptosis through increasing the expression of GPX4, which provides a rationale administrating DPX for the treatment of ICH targeting ferroptosis.…”

“…Thereafter, a negative loop between GPX4 and lipid peroxidation determines the fate of neural cells after injury. Here, GPX4 is downregulated with the presence of elevated lipid peroxidation at perihematomal site after ICH, which is consistent with previous studies [43][44][45][46]. Meanwhile, the results also report that GPX4 upregulation induced by the administration of DPX alleviates lipid peroxidation injury to neural cells after ICH, which is in line with previous studies that elevated GPX4 expression mitigates ICH-induced acute brain injury by activating ferroptosis [44,46,47].…”

OIT3 serves as a novel biomarker of hepatocellular carcinoma by mediating ferroptosis via regulating the arachidonic acid metabolism

“…The auto-oxidation of AA could even contribute to lipid peroxidation in the acetaminophen-induced ferroptosis process in liver tissue ( 44 ). Accordingly, inhibiting the synthesis of AA could have a protective effect on ferroptosis ( 45 ). AA has been identified as the direct precursor of various types of bioactive mediators, including leukotrienes (LTs), such as LTB4, LTC4, and so on.…”

Elucidating the progress and impact of ferroptosis in hemorrhagic stroke

“…The high level of PUFAs in the brain is beneficial for inducing ferroptosis signaling in ICH. 20-hydroxyeicosatetraenoic acid (20-HETE), a metabolite of ADA, was recently shown to be involved in neuronal ferroptosis upon ICH induction in mice ( Han et al, 2021 ). And reduction of its production with the specific inhibitor HET0016 significantly inhibited lipid peroxidation levels and cell death in an in vitro model of ICH ( Han et al, 2021 ).…”

“…20-hydroxyeicosatetraenoic acid (20-HETE), a metabolite of ADA, was recently shown to be involved in neuronal ferroptosis upon ICH induction in mice ( Han et al, 2021 ). And reduction of its production with the specific inhibitor HET0016 significantly inhibited lipid peroxidation levels and cell death in an in vitro model of ICH ( Han et al, 2021 ). This significantly contributed to research on lipid peroxidation in ferroptosis after ICH due to limited previous research exploring this direct relationship.…”