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COX-2/PGE2 Pathway Inhibits the Ferroptosis Induced by Cerebral Ischemia Reperfusion

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A Correction to this article was published on 08 October 2022

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Abstract

Cerebral ischemia reperfusion (I/R) injury easily develops in ischemic stroke, resulting in more serious injury. Ferroptosis is involved in cerebral I/R injury, but the mechanism remains unclear. Prostaglandin E2 (PGE2) is potential to regulate ferroptosis. This study mainly explored the regulation effects of PGE2 on ferroptosis induced by cerebral I/R. We first detected PGE2 levels and ferroptosis status in 11 human brain tissues. Then, we induced a cerebral I/R animal model to examine ferroptosis status in cerebral I/R. We further injected a ferroptosis inhibitor to define the response of the PGE2 pathway to ferroptosis. Finally, we injected PGE2 and pranoprofen to explore the regulation of the cyclooxygenases 2 (COX-2)/PGE2 pathway on ferroptosis in cerebral I/R. We found that PGE2 release was correlated with the levels of reactive oxygen species, malondialdehyde, glutathione peroxidase 4, COX-2, and Spermidine/spermine N1-acetyltransferase 1. Ferroptosis can be induced by cerebral I/R, while inhibition of ferroptosis induced by cerebral I/R can inactivate PGE2 synthases, degrade enzyme, and parts of PGE2 receptors, and reduce cerebral infarct volume. In turn, PGE2 inhibited ferroptosis through the reduction of Fe2+, glutathione oxidation, and lipid peroxidation, while pranoprofen, one of the COX inhibitors, played an opposite role. In conclusion, PGE2 was positively correlated with ferroptosis, inhibition of ferroptosis induced by cerebral I/R can inactivate COX-2/PGE2 pathway, and PGE2 inhibited ferroptosis induced by cerebral I/R, possibly via PGE2 receptor 3 and PGE2 receptor 4.

Inhibition of ferroptosis inactivates the COX-2/PGE2 pathway. Cerebral ischemia reperfusion injury induces the secretion of PGE2. After the inhibition of ferroptosis by Fer-1, the expression of cyclooxygenases (COX-1 and COX-2) decreased, and PGE2 synthases cPGES, mPGES-1, and mPGES-2 were also reduced. At the same time, the PGE2 degradation enzyme 15-PGDH was also reduced. Changes in these enzymes ultimately result in the declination of PGE2. Besides, the expression of PGE2 receptors EP3 and EP4 is also inhibited, indicating that the function they mediate is also impaired. In conclusion, after cerebral ischemia reperfusion injury, the inhibition of ferroptosis inactivates the COX-2/PGE2 pathway

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Acknowledgements

We thank the patients for granting permission to publish this information.

Funding

This work was supported by the National Natural Science Foundation of China (No. 81571880, 81373147, 30901555, 30972870, 81360080) and the Natural Science Foundation of Hunan Province (2016JJ2157), the Fundamental Research Funds for the Central Universities of Central South University (2020zzts222). All the funding bodies funded in the study design, collection, analysis, interpretation of data, and writing the manuscript.

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  1. Yunfei Xu and Ying Liu are contributed equally in this work.

Authors and Affiliations

  1. Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China

    Yunfei Xu, Ying Liu, Kexin Li, Dun Yuan, Shun Yang, Lin Zhou, Yao Zhao, Caihong Lv & Jie Zhao

  2. Department of Pathophysiology, Xiangya School of Medicine, Central South University, Changsha, 410008, Hunan, China

    Yunfei Xu, Ying Liu, Kexin Li, Lin Zhou, Yao Zhao & Caihong Lv

  3. Sepsis Translational Medicine Key Lab of Hunan Province, Changsha, 410008, Hunan, China

    Yunfei Xu, Ying Liu, Kexin Li, Lin Zhou, Yao Zhao, Caihong Lv & Jie Zhao

  4. China-Africa Research Center of Infectious Diseases, Central South University, Changsha, China

    Yunfei Xu, Ying Liu, Kexin Li, Lin Zhou, Yao Zhao, Shuying Miao, Caihong Lv & Jie Zhao

  5. Department of Pathology, Nanjing Drum Tower Hospital, Nanjing University Medical School, Nanjing, 210008, Jiangsu, China

    Shuying Miao

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Contributions

Ying Liu and Jie Zhao designed and directed the project. Dun Yuan and Shun Yang collected clinical samples. Yunfei Xu and Kexin Li performed the experiments. Yunfei Xu, Kexin Li, Lin Zhou, Yao Zhao, Shuying Miao, and Caihong Lv analyzed the data. All authors discussed the results and contributed to the final manuscript. Yunfei Xu wrote the manuscript.

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Correspondence to Ying Liu or Jie Zhao.

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All applicable international, national, and/or institutional guidelines for the care and use of animals were followed. This research was approved by the ethics committee of the Xiangya Hospital of Central South University, No: 2021101119. All participants involved in this study provided written informed consent. All procedures performed in studies involving animals were by the ethical standards of the institution or practice at which the studies were conducted by Experimental Animal Center of Central South University (Changsha, China), No: 2018sydw0222.

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Xu, Y., Liu, Y., Li, K. et al. COX-2/PGE2 Pathway Inhibits the Ferroptosis Induced by Cerebral Ischemia Reperfusion. Mol Neurobiol 59, 1619–1631 (2022). https://doi.org/10.1007/s12035-021-02706-1

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