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

Autor:	Lei B; Department of Cerebrovascular Disease, People's Hospital of Leshan, Leshan City, Sichuan provincial, China., Wu H; Department of Cerebrovascular Disease, People's Hospital of Leshan, Leshan City, Sichuan provincial, China., You G; Department of Cerebrovascular Disease, People's Hospital of Leshan, Leshan City, Sichuan provincial, China., Wan X; Department of Cerebrovascular Disease, People's Hospital of Leshan, Leshan City, Sichuan provincial, China., Chen S; Department of Cerebrovascular Disease, People's Hospital of Leshan, Leshan City, Sichuan provincial, China., Chen L; Department of Cerebrovascular Disease, People's Hospital of Leshan, Leshan City, Sichuan provincial, China., Wu J; Department of Cerebrovascular Disease, People's Hospital of Leshan, Leshan City, Sichuan provincial, China., Zheng N; Department of Cerebrovascular Disease, People's Hospital of Leshan, Leshan City, Sichuan provincial, China.
Jazyk:	angličtina
Zdroj:	Biotechnology & genetic engineering reviews [Biotechnol Genet Eng Rev] 2024 Dec; Vol. 40 (4), pp. 4341-4360. Date of Electronic Publication: 2023 May 08.
DOI:	10.1080/02648725.2023.2210449
Abstrakt:	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.
Databáze:	MEDLINE
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