1. Academic Validation
  2. Silencing of ALOX15 reduces ferroptosis and inflammation induced by cerebral ischemia-reperfusion by regulating PHD2/HIF2α signaling pathway

Silencing of ALOX15 reduces ferroptosis and inflammation induced by cerebral ischemia-reperfusion by regulating PHD2/HIF2α signaling pathway

  • Biotechnol Genet Eng Rev. 2023 May 8;1-19. doi: 10.1080/02648725.2023.2210449.
Bo Lei 1 Honggang Wu 1 Guoliang You 1 Xiaoqiang Wan 1 Shu Chen 1 Li Chen 1 Jiachuan Wu 1 Niandong Zheng 1
Affiliations

Affiliation

  • 1 Department of Cerebrovascular Disease, People's Hospital of Leshan, Leshan City, Sichuan provincial, China.
Abstract

Objective: To investigate the potential mechanism of arachidonic acid deoxyribozyme 15 (ALOX15) in Ferroptosis and inflammation induced by cerebral ischemia reperfusion injury.

Methods: The mice and cell models of cerebral ischemia-reperfusion injury were constructed. Western Blot was used to detect the protein expression levels of ALOX15, Glutathione Peroxidase (GPX4), hypoxia-inducible factor-2α (HIF-2α), prolyl hydroxylase (PHD) and inflammatory factors (NLRP3, IL-1β, IL-18) in brain tissues and cells. Cell proliferation activity was detected by CCK-8 method. LDH assay was used to detect the release of Lactate Dehydrogenase. TTC staining was used to observe cerebral infarction.

Results: In cerebral ischemia-reperfusion mice and cell models, the expression of ALOX15 protein was increased, the expression of GPX4, a key marker of Ferroptosis was decreased, and silencing of ALOX15 down-regulated the GPX4 expression. HIF-2α expression was down-regulated in animal and cell models of cerebral ischemia reperfusion, and silencing of ALOX15 increased the HIF-2α expression by inhibiting PHD2 expression. Inhibition of ALOX15 expression reduced inflammatory factors levels (NLRP3, IL-1β, and IL-18) in cerebral ischemia. Inhibitor of PHD2 (IXOC-4) alleviating brain injury and cell death induced by cerebral ischemia reperfusion and stabilize HIF-2α expression in vivo.

Conclusion: The expression of ALOX15 was up-regulated in cerebral ischemia-reperfusion Animals and cells model. Inhibition of ALOX15 up-regulated the GPX4 expression, and promoted HIF-2α expression by inhibiting PHD2, thus alleviating Ferroptosis and inflammation caused by cerebral ischemia-reperfusion injury.

Keywords

ALOX15; Cerebral ischemia-reperfusion; HIF-2α; Inflammation; PHD2.

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