Inhibition of 15‐hydroxyprostaglandin dehydrogenase protects neurons from ferroptosis in ischemic stroke
Abstract Ischemic stroke is an acute serious cerebrovascular disease with high mortality and disability. Ferroptosis is an important regulated cell death (RCD) in ischemic stroke. 15‐Hydroxyprostaglandin dehydrogenase (15‐PGDH), a degrading enzyme of prostaglandin E2 (PGE2), is shown to regulate RCD...
| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Wiley
2024-01-01
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| Series: | MedComm |
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| Online Access: | https://doi.org/10.1002/mco2.452 |
| _version_ | 1827375009216069632 |
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| author | Yunfei Xu Kexin Li Yao Zhao Lin Zhou Nina He Haoduo Qiao Qing Xu Huali Zhang Ying Liu Jie Zhao |
| author_facet | Yunfei Xu Kexin Li Yao Zhao Lin Zhou Nina He Haoduo Qiao Qing Xu Huali Zhang Ying Liu Jie Zhao |
| author_sort | Yunfei Xu |
| collection | DOAJ |
| description | Abstract Ischemic stroke is an acute serious cerebrovascular disease with high mortality and disability. Ferroptosis is an important regulated cell death (RCD) in ischemic stroke. 15‐Hydroxyprostaglandin dehydrogenase (15‐PGDH), a degrading enzyme of prostaglandin E2 (PGE2), is shown to regulate RCD such as autophagy and apoptosis. The study aimed to determine whether 15‐PGDH regulates ferroptosis and ischemic stroke, and further the exact mechanism. We demonstrated that overexpression of 15‐PGDH in the brain tissues or primary cultured neurons significantly aggravated cerebral injury and neural ferroptosis in ischemic stroke. While inhibition of 15‐PGDH significantly protected against cerebral injury and neural ferroptosis, which benefits arise from the activation of the PGE2/PGE2 receptor 4 (EP4) axis. While the impact of 15‐PGDH was abolished with glutathione peroxidase 4 (GPX4) deficiency. Then, 15‐PGDH inhibitor was found to promote the activation of cAMP‐response element‐binding protein (CREB) and nuclear factor kappa‐B (NF‐κB) via the PGE2/EP4 axis, subsequently transcriptionally upregulate the expression of GPX4. In summary, our study indicates that inhibition of 15‐PGDH promotes the activation PGE2/EP4 axis, subsequently transcriptionally upregulates the expression of GPX4 via CREB and NF‐κB, and then protects neurons from ferroptosis and alleviates the ischemic stroke. Therefore, 15‐PGDH may be a potential therapeutic target for ischemic stroke. |
| first_indexed | 2024-03-08T11:43:27Z |
| format | Article |
| id | doaj.art-6292ec55fbe5435ebe56cd3a07da8d67 |
| institution | Directory Open Access Journal |
| issn | 2688-2663 |
| language | English |
| last_indexed | 2024-03-08T11:43:27Z |
| publishDate | 2024-01-01 |
| publisher | Wiley |
| record_format | Article |
| series | MedComm |
| spelling | doaj.art-6292ec55fbe5435ebe56cd3a07da8d672024-01-25T02:14:28ZengWileyMedComm2688-26632024-01-0151n/an/a10.1002/mco2.452Inhibition of 15‐hydroxyprostaglandin dehydrogenase protects neurons from ferroptosis in ischemic strokeYunfei Xu0Kexin Li1Yao Zhao2Lin Zhou3Nina He4Haoduo Qiao5Qing Xu6Huali Zhang7Ying Liu8Jie Zhao9Department of Pathophysiology School of Basic Medical Sciences Central South University Changsha Hunan ChinaDepartment of Pathophysiology School of Basic Medical Sciences Central South University Changsha Hunan ChinaDepartment of Pathophysiology School of Basic Medical Sciences Central South University Changsha Hunan ChinaDepartment of Pathophysiology School of Basic Medical Sciences Central South University Changsha Hunan ChinaDepartment of Pathophysiology School of Basic Medical Sciences Central South University Changsha Hunan ChinaDepartment of Pathophysiology School of Basic Medical Sciences Central South University Changsha Hunan ChinaDepartment of Pathophysiology School of Basic Medical Sciences Central South University Changsha Hunan ChinaDepartment of Pathophysiology School of Basic Medical Sciences Central South University Changsha Hunan ChinaDepartment of Pathophysiology School of Basic Medical Sciences Central South University Changsha Hunan ChinaDepartment of Neurosurgery Xiangya Hospital Central South University Changsha Hunan ChinaAbstract Ischemic stroke is an acute serious cerebrovascular disease with high mortality and disability. Ferroptosis is an important regulated cell death (RCD) in ischemic stroke. 15‐Hydroxyprostaglandin dehydrogenase (15‐PGDH), a degrading enzyme of prostaglandin E2 (PGE2), is shown to regulate RCD such as autophagy and apoptosis. The study aimed to determine whether 15‐PGDH regulates ferroptosis and ischemic stroke, and further the exact mechanism. We demonstrated that overexpression of 15‐PGDH in the brain tissues or primary cultured neurons significantly aggravated cerebral injury and neural ferroptosis in ischemic stroke. While inhibition of 15‐PGDH significantly protected against cerebral injury and neural ferroptosis, which benefits arise from the activation of the PGE2/PGE2 receptor 4 (EP4) axis. While the impact of 15‐PGDH was abolished with glutathione peroxidase 4 (GPX4) deficiency. Then, 15‐PGDH inhibitor was found to promote the activation of cAMP‐response element‐binding protein (CREB) and nuclear factor kappa‐B (NF‐κB) via the PGE2/EP4 axis, subsequently transcriptionally upregulate the expression of GPX4. In summary, our study indicates that inhibition of 15‐PGDH promotes the activation PGE2/EP4 axis, subsequently transcriptionally upregulates the expression of GPX4 via CREB and NF‐κB, and then protects neurons from ferroptosis and alleviates the ischemic stroke. Therefore, 15‐PGDH may be a potential therapeutic target for ischemic stroke.https://doi.org/10.1002/mco2.45215‐PGDHferroptosisGPX4ischemic strokePGE2 |
| spellingShingle | Yunfei Xu Kexin Li Yao Zhao Lin Zhou Nina He Haoduo Qiao Qing Xu Huali Zhang Ying Liu Jie Zhao Inhibition of 15‐hydroxyprostaglandin dehydrogenase protects neurons from ferroptosis in ischemic stroke MedComm 15‐PGDH ferroptosis GPX4 ischemic stroke PGE2 |
| title | Inhibition of 15‐hydroxyprostaglandin dehydrogenase protects neurons from ferroptosis in ischemic stroke |
| title_full | Inhibition of 15‐hydroxyprostaglandin dehydrogenase protects neurons from ferroptosis in ischemic stroke |
| title_fullStr | Inhibition of 15‐hydroxyprostaglandin dehydrogenase protects neurons from ferroptosis in ischemic stroke |
| title_full_unstemmed | Inhibition of 15‐hydroxyprostaglandin dehydrogenase protects neurons from ferroptosis in ischemic stroke |
| title_short | Inhibition of 15‐hydroxyprostaglandin dehydrogenase protects neurons from ferroptosis in ischemic stroke |
| title_sort | inhibition of 15 hydroxyprostaglandin dehydrogenase protects neurons from ferroptosis in ischemic stroke |
| topic | 15‐PGDH ferroptosis GPX4 ischemic stroke PGE2 |
| url | https://doi.org/10.1002/mco2.452 |
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