PMID- 36681202 OWN - NLM STAT- MEDLINE DCOM- 20230206 LR - 20230222 IS - 1873-4596 (Electronic) IS - 0891-5849 (Linking) VI - 196 DP - 2023 Feb 20 TI - Elabela-APJ axis attenuates cerebral ischemia/reperfusion injury by inhibiting neuronal ferroptosis. PG - 171-186 LID - S0891-5849(23)00009-6 [pii] LID - 10.1016/j.freeradbiomed.2023.01.008 [doi] AB - Ferroptosis is a form of non-apoptotic cell death caused by iron-dependent peroxidation of lipids. It contributes to ischemic stroke-induced neuronal damage. Elabela (ELA), a novel endogenous ligand for Apelin receptor (APJ), regulates oxidative stress and exerts a protective role in cardiovascular disease. However, the effect of ELA-APJ axis on cellular ferroptosis in cerebral ischemia/reperfusion (I/R) remains elusive. The present study showed that ELA and APJ were expressed on neurons and increased after cerebral I/R injury. The I/R insult triggered typical molecular and morphological features of neuronal ferroptosis, including iron and MDA accumulation, mitochondrial shrink and membrane rupture, upregulation of positive ferroptosis regulators and downregulation of negative regulators. ELA-32 treatment reduced brain infarction and ameliorated neurobehavioral deficits and cognitive dysfunction. Moreover, ELA-32 administration alleviated neuronal ferroptosis, accompanied by reduced iron deposition, decreased mitochondrial damage, relived lipid peroxidation and glutathione reduction. Such effects of ELA-32 were abolished by AAV-APJ-RNAi or nuclear factor erythroid 2-related factor 2 (NRF2) inhibitor ML385. Mechanistically, ELA was shown to bind to APJ and activate NRF2/ARE anti-oxidative signaling pathway via Galpha13. Together, these findings suggested that ELA-APJ axis mitigates neuronal ferroptosis after ischemic stroke and that the ELA-32 peptide may be a putative therapeutic avenue for ischemic stroke. CI - Copyright (c) 2023 Elsevier Inc. All rights reserved. FAU - Xu, Pengfei AU - Xu P AD - Department of Neurology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, 230001, China. FAU - Kong, Lingqi AU - Kong L AD - Department of Neurology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, 230001, China. FAU - Tao, Chunrong AU - Tao C AD - Department of Neurology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, 230001, China. FAU - Zhu, Yuyou AU - Zhu Y AD - Department of Neurology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, 230001, China. FAU - Cheng, Juan AU - Cheng J AD - Department of Neurology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, 230001, China. FAU - Li, Wenyu AU - Li W AD - Department of Neurology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, 230001, China. FAU - Shen, Nan AU - Shen N AD - Department of Neurology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, 230001, China. FAU - Li, Rui AU - Li R AD - Department of Neurology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, 230001, China. FAU - Zhang, Chao AU - Zhang C AD - Department of Neurology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, 230001, China. FAU - Wang, Li AU - Wang L AD - Department of Neurology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, 230001, China. FAU - Zhang, Yan AU - Zhang Y AD - Department of Neurology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, 230001, China. FAU - Wang, Guoping AU - Wang G AD - Department of Neurology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, 230001, China. FAU - Liu, Xinfeng AU - Liu X AD - Department of Neurology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, 230001, China. Electronic address: xfliu2@ustc.edu.cn. FAU - Sun, Wen AU - Sun W AD - Department of Neurology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, 230001, China. Electronic address: sunwen_medneuro@163.com. FAU - Hu, Wei AU - Hu W AD - Department of Neurology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, 230001, China. Electronic address: andinghu@ustc.edu.cn. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20230118 PL - United States TA - Free Radic Biol Med JT - Free radical biology & medicine JID - 8709159 RN - 0 (NF-E2-Related Factor 2) SB - IM MH - Humans MH - *Ferroptosis/genetics MH - NF-E2-Related Factor 2/genetics MH - Neurons MH - *Reperfusion Injury/genetics MH - *Ischemic Stroke MH - *Brain Ischemia/genetics OTO - NOTNLM OT - APJ OT - Elabela OT - Ferroptosis OT - Ischemia/reperfusion OT - NRF2 COIS- Declaration of competing interest The authors declare that they have no competing interests. EDAT- 2023/01/22 06:00 MHDA- 2023/02/07 06:00 CRDT- 2023/01/21 19:25 PHST- 2022/10/16 00:00 [received] PHST- 2022/12/27 00:00 [revised] PHST- 2023/01/08 00:00 [accepted] PHST- 2023/01/22 06:00 [pubmed] PHST- 2023/02/07 06:00 [medline] PHST- 2023/01/21 19:25 [entrez] AID - S0891-5849(23)00009-6 [pii] AID - 10.1016/j.freeradbiomed.2023.01.008 [doi] PST - ppublish SO - Free Radic Biol Med. 2023 Feb 20;196:171-186. doi: 10.1016/j.freeradbiomed.2023.01.008. Epub 2023 Jan 18.