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 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.

Keywords

15-PGDH / ferroptosis / GPX4 / ischemic stroke / PGE2

References

[1] Global, regional, and national burden of stroke and its risk factors, 1990–2019: a systematic analysis for the Global Burden of Disease Study 2019. Lancet Neurol. 2021;20(10):795-820.

[2] Feske SK. Ischemic stroke. Am J Med. 2021;134(12):1457-1464.

[3] Xu Y, Li K, Zhao Y, Zhou L, Liu Y, Zhao J. Role of ferroptosis in stroke. Cell Mol Neurobiol. 2022;43(1):205-222.

[4] Powers WJ, Rabinstein AA, Ackerson T, et al. 2018 Guidelines for the early management of patients with acute ischemic stroke: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke. 2018;49(3):e46-e110.

[5] Dixon SJ, Lemberg KM, Lamprecht MR, et al. Ferroptosis: an iron-dependent form of nonapoptotic cell death. Cell. 2012;149(5):1060-1072.

[6] Li Y, Feng D, Wang Z, et al. Ischemia-induced ACSL4 activation contributes to ferroptosis-mediated tissue injury in intestinal ischemia/reperfusion. Cell Death Differ. 2019;26(11):2284-2299.

[7] Cao JY, Dixon SJ. Mechanisms of ferroptosis. Cell Mol Life Sci. 2016;73(11-12):2195-2209.

[8] Li J, Cao F, Yin HL, et al. Ferroptosis: past, present and future. Cell Death Dis. 2020;11(2):88.

[9] Han Y, Zhu J, Yang L, et al. SARS-CoV-2 infection induces ferroptosis of sinoatrial node pacemaker cells. Circ Res. 2022;130(7):963-977.

[10] Yan B, Guo J, Wang Z, et al. The ubiquitin-specific protease 5 mediated deubiquitination of LSH links metabolic regulation of ferroptosis to hepatocellular carcinoma progression. MedComm. 2023;4(4):e337.

[11] Long H, Zhu W, Wei L, Zhao J. Iron homeostasis imbalance and ferroptosis in brain diseases. MedComm. 2023;4(4):e298.

[12] Palla AR, Ravichandran M, Wang YX, et al. Inhibition of prostaglandin-degrading enzyme 15-PGDH rejuvenates aged muscle mass and strength. Science. 2021;371(6528):eabc8059.

[13] Ricke-Hoch M, Stelling E, Lasswitz L, et al. Impaired immune response mediated by prostaglandin E2 promotes severe COVID-19 disease. PLoS One. 2021;16(8):e0255335.

[14] Zhang Y, Desai A, Yang SY, et al. Tissue regeneration. Inhibition of the prostaglandin-degrading enzyme 15-PGDH potentiates tissue regeneration. Science. 2015;348(6240):aaa2340.

[15] Xu Y, Liu Y, Li K, et al. COX-2/PGE2 pathway inhibits the ferroptosis induced by cerebral ischemia reperfusion. Mol Neurobiol. 2022;59(3):1619-1631.

[16] Xu Y, Liu Y, Li K, et al. Regulation of PGE(2) pathway during cerebral ischemia reperfusion injury in rat. Cell Mol Neurobiol. 2021;41(7):1483-1496.

[17] Alim I, Caulfield JT, Chen Y, et al. Selenium drives a transcriptional adaptive program to block ferroptosis and treat stroke. Cell. 2019;177(5):1262-1279.e25.

[18] Zhu L, Zhang Y, Guo Z, Wang M. Cardiovascular biology of prostanoids and drug discovery. Arterioscler Thromb Vasc Biol. 2020;40(6):1454-1463.

[19] Takeuchi K, Amagase K. Roles of cyclooxygenase, prostaglandin E2 and EP receptors in mucosal protection and ulcer healing in the gastrointestinal tract. Curr Pharm Des. 2018;24(18):2002-2011.

[20] Lebender LF, Prünte L, Rumzhum NN, Ammit AJ. Selectively targeting prostanoid E (EP) receptor-mediated cell signalling pathways: implications for lung health and disease. Pulm Pharmacol Ther. 2018;49:75-87.

[21] Heeney A, Rogers AC, Mohan H, Mc Dermott F, Baird AW, Winter DC. Prostaglandin E(2) receptors and their role in gastrointestinal motility—Potential therapeutic targets. Prostaglandins Other Lipid Mediat. 2021;152:106499.

[22] Tong D, Liu Q, Wang LA, et al. The roles of the COX2/PGE2/EP axis in therapeutic resistance. Cancer Metastasis Rev. 2018;37(2-3):355-368.

[23] Tsuge K, Inazumi T, Shimamoto A, Sugimoto Y. Molecular mechanisms underlying prostaglandin E2-exacerbated inflammation and immune diseases. Int Immunol. 2019;31(9):597-606.

[24] DeMars KM, McCrea AO, Siwarski DM, Sanz BD, Yang C, Candelario-Jalil E. Protective effects of L-902,688, a prostanoid EP4 receptor agonist, against acute blood-brain barrier damage in experimental ischemic stroke. Front Neurosci. 2018;12:89.

[25] Jin Y, Liu Q, Chen P, et al. A novel prostaglandin E receptor 4 (EP4) small molecule antagonist induces articular cartilage regeneration. Cell Discov. 2022;8(1):24.

[26] Bryson TD, Ross J, Peterson E, Harding P. Prostaglandin E(2) and an EP4 receptor agonist inhibit LPS-Induced monocyte chemotactic protein 5 production and secretion in mouse cardiac fibroblasts via Akt and NF-κB signaling. Prostaglandins Other Lipid Mediat. 2019;144:106349.

[27] Yao L, Chen W, Song K, et al. 15-hydroxyprostaglandin dehydrogenase (15-PGDH) prevents lipopolysaccharide (LPS)-induced acute liver injury. PLoS One. 2017;12(4):e0176106.

[28] Miao S, Lv C, Liu Y, et al. Pharmacologic blockade of 15-PGDH protects against acute renal injury induced by LPS in mice. Front Physiol. 2020;11:138.

[29] Wang D, Liu Y, Lu P, Zhu D, Zhu Y. 15-oxo-ETE-induced internal carotid artery constriction in hypoxic rats is mediated by potassium channels. Physiol Res. 2016;65(3):391-399.

[30] Kim HJ, Kim SH, Kim M, et al. Inhibition of 15-PGDH prevents ischemic renal injury by the PGE(2)/EP(4) signaling pathway mediating vasodilation, increased renal blood flow, and increased adenosine/A(2A) receptors. Am J Physiol Renal Physiol. 2020;319(6):F1054-F1066.

[31] Wen H, He R, Wang H, et al. Effects of small molecule inhibitor SW033291 on hepatic ischemia-reperfusion injury in mice. Biochem Biophys Res Commun. 2022;615:70-74.

[32] Monteleone NJ, Moore AE, Iacona JR, Lutz CS, Dixon DA. miR-21-mediated regulation of 15-hydroxyprostaglandin dehydrogenase in colon cancer. Sci Rep. 2019;9(1):5405.

[33] Arima K, Komohara Y, Bu L, et al. Downregulation of 15-hydroxyprostaglandin dehydrogenase by interleukin-1β from activated macrophages leads to poor prognosis in pancreatic cancer. Cancer Sci. 2018;109(2):462-470.

[34] Arima K, Ohmuraya M, Miyake K, et al. Inhibition of 15-PGDH causes Kras-driven tumor expansion through prostaglandin E2-ALDH1 signaling in the pancreas. Oncogene. 2019;38(8):1211-1224.

[35] Liang C, Zhang X, Yang M, Dong X. Recent progress in ferroptosis inducers for cancer therapy. Adv Mater. 2019;31(51):e1904197.

[36] Ding Y, Chen X, Liu C, et al. Identification of a small molecule as inducer of ferroptosis and apoptosis through ubiquitination of GPX4 in triple negative breast cancer cells. J Hematol Oncol. 2021;14(1):19.

[37] Bygdeman M. Pharmacokinetics of prostaglandins. Best Pract Res Clin Obstet Gynaecol. 2003;17(5):707-716.

[38] Chen H, Hu B, Lv X, et al. Prostaglandin E2 mediates sensory nerve regulation of bone homeostasis. Nat Commun. 2019;10(1):181.

[39] Smith JN, Dawson DM, Christo KF, et al. 15-PGDH inhibition activates the splenic niche to promote hematopoietic regeneration. JCI Insight. 2021;6(6):e143658.

[40] Zhan C, Lin G, Huang Y, Wang Z, Zeng F, Wu S. A dopamine-precursor-based nanoprodrug for in-situ drug release and treatment of acute liver failure by inhibiting NLRP3 inflammasome and facilitating liver regeneration. Biomaterials. 2021;268:120573.

[41] Bersuker K, Hendricks JM, Li Z, et al. The CoQ oxidoreductase FSP1 acts parallel to GPX4 to inhibit ferroptosis. Nature. 2019;575(7784):688-692.

[42] Doll S, Freitas FP, Shah R, et al. FSP1 is a glutathione-independent ferroptosis suppressor. Nature. 2019;575(7784):693-698.

[43] Kraft VAN, Bezjian CT, Pfeiffer S, et al. GTP cyclohydrolase 1/tetrahydrobiopterin counteract ferroptosis through lipid remodeling. ACS Cent Sci. 2020;6(1):41-53.

[44] Dai E, Zhang W, Cong D, Kang R, Wang J, Tang D. AIFM2 blocks ferroptosis independent of ubiquinol metabolism. Biochem Biophys Res Commun. 2020;523(4):966-971.

[45] Mao C, Liu X, Zhang Y, et al. DHODH-mediated ferroptosis defence is a targetable vulnerability in cancer. Nature. 2021;593(7860):586-590.

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