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已发表论文
艾塞那肽 - 4 刺激的内皮细胞分泌的外泌体 miR - 450b - 5p 可保护视网膜神经节细胞免受缺血再灌注损伤
Authors Sun Y, Zhai R, Sheng Q, Ying Y, Kwan YL, Fan X, Xu H , Kong X
Received 23 March 2025
Accepted for publication 5 July 2025
Published 25 September 2025 Volume 2025:20 Pages 11881—11894
DOI https://doi.org/10.2147/IJN.S525339
Checked for plagiarism Yes
Review by Single anonymous peer review
Peer reviewer comments 3
Editor who approved publication: Dr Kamakhya Misra
Yanan Sun,1,2,* Ruyi Zhai,1,* Qilian Sheng,1,* Yue Ying,1,* Ye Lin Kwan,1 Xintong Fan,1 Huan Xu,1 Xiangmei Kong1
1Eye Institute and Department of Ophthalmology, Eye & ENT Hospital, Fudan University, National Health Commission Key Laboratory of Myopia (Fudan University), Key Laboratory of Myopia, Chinese Academy of Medical Sciences, Shanghai Key Laboratory of Visual Impairment and Restoration, Shanghai, People’s Republic of China; 2Shenzhen Eye Hospital, Shenzhen Eye Medical Center, Southern Medical University, Shenzhen, People’s Republic of China
*These authors contributed equally to this work
Correspondence: Xiangmei Kong, Eye Institute and Department of Ophthalmology, Eye & ENT Hospital, Fudan University, 83 Fenyang Road, Xuhui District, Shanghai, 200031, People’s Republic of China, Tel +86 2164377134, Email kongxm95@163.com Huan Xu, Eye Institute and Department of Ophthalmology, Eye & ENT Hospital, Fudan University, 83 Fenyang Road, Xuhui District, Shanghai, 200031, People’s Republic of China, Tel +86 2164377134, Email xuhuan320@163.com
Background: Retinal ischemia-reperfusion (RIR) injury represents a critical pathophysiological mechanism underlying various ocular ischemic diseases, characterized by progressive loss of retinal ganglion cells (RGCs). Exendin-4 (Ex-4), a widely used glucagon-like peptide-1 receptor (GLP-1R) agonist drug in the treatment of type 2 diabetes mellitus, has been reported to protect against ischemia-reperfusion (IR) injury in various vital organs. However, the potential neuroprotective effect of Ex-4 under RIR injury has been poorly understood.
Methods: Immunofluorescence staining assay, hematoxylin and eosin (HE) staining were conducted to evaluate the neuroprotective role of Ex-4. A co-culture assay of human retinal vascular endothelial cells (HRVECs) and RGCs was established. Extracellular vesicles (EVs) were isolated from the culture supernatant of HRVECs with (E-EVs) or without Ex-4 treatment (O-EVs) under oxygen-glucose deprivation/reoxygenation (OGD/R) condition. Transmission electron microscopy (TEM), Nanoparticle tracking analysis (NTA) and Nano-flow cytometry (NanoFCM) were used to detect the presence and purity of EVs. Cell activity, reactive oxygen species (ROS) level, and cell death rate of RGCs were evaluated. Further global miRNA sequencing was performed on E-EVs or O-EVs to explore potential mechanisms.
Results: Our findings revealed that Ex-4 had a GLP-1R-dependent neuroprotective effect on RGCs. Vascular endothelial cells (VECs) -derived EVs mediate the protective effect of Ex-4 on RGCs under acute RIR injury. We identified miR-450b-5p as a highly enriched miRNA in E-EVs. Treatment with either E-EVs or miR-450b-5p mimics significantly protected RGCs against RIR-induced injury. Mechanistic investigations identified acyl-coenzyme A (CoA) synthetase long-chain family member 4 (ACSL4) as a direct target of miR-450b-5p.
Conclusion: Ex-4 exerts its neuroprotective effects under RIR injury by stimulating retinal VECs to secrete miR-450b-5p-enriched EVs, thereby revealing a novel endothelial-mediated neuroprotective pathway in ischemia diseases.
Keywords: exendin-4, retinal ganglion cells, ischemia reperfusion injury, retinal vascular endothelial cells, extracellular vesicles, microRNA
1Eye Institute and Department of Ophthalmology, Eye & ENT Hospital, Fudan University, National Health Commission Key Laboratory of Myopia (Fudan University), Key Laboratory of Myopia, Chinese Academy of Medical Sciences, Shanghai Key Laboratory of Visual Impairment and Restoration, Shanghai, People’s Republic of China; 2Shenzhen Eye Hospital, Shenzhen Eye Medical Center, Southern Medical University, Shenzhen, People’s Republic of China
*These authors contributed equally to this work
Correspondence: Xiangmei Kong, Eye Institute and Department of Ophthalmology, Eye & ENT Hospital, Fudan University, 83 Fenyang Road, Xuhui District, Shanghai, 200031, People’s Republic of China, Tel +86 2164377134, Email kongxm95@163.com Huan Xu, Eye Institute and Department of Ophthalmology, Eye & ENT Hospital, Fudan University, 83 Fenyang Road, Xuhui District, Shanghai, 200031, People’s Republic of China, Tel +86 2164377134, Email xuhuan320@163.com
Background: Retinal ischemia-reperfusion (RIR) injury represents a critical pathophysiological mechanism underlying various ocular ischemic diseases, characterized by progressive loss of retinal ganglion cells (RGCs). Exendin-4 (Ex-4), a widely used glucagon-like peptide-1 receptor (GLP-1R) agonist drug in the treatment of type 2 diabetes mellitus, has been reported to protect against ischemia-reperfusion (IR) injury in various vital organs. However, the potential neuroprotective effect of Ex-4 under RIR injury has been poorly understood.
Methods: Immunofluorescence staining assay, hematoxylin and eosin (HE) staining were conducted to evaluate the neuroprotective role of Ex-4. A co-culture assay of human retinal vascular endothelial cells (HRVECs) and RGCs was established. Extracellular vesicles (EVs) were isolated from the culture supernatant of HRVECs with (E-EVs) or without Ex-4 treatment (O-EVs) under oxygen-glucose deprivation/reoxygenation (OGD/R) condition. Transmission electron microscopy (TEM), Nanoparticle tracking analysis (NTA) and Nano-flow cytometry (NanoFCM) were used to detect the presence and purity of EVs. Cell activity, reactive oxygen species (ROS) level, and cell death rate of RGCs were evaluated. Further global miRNA sequencing was performed on E-EVs or O-EVs to explore potential mechanisms.
Results: Our findings revealed that Ex-4 had a GLP-1R-dependent neuroprotective effect on RGCs. Vascular endothelial cells (VECs) -derived EVs mediate the protective effect of Ex-4 on RGCs under acute RIR injury. We identified miR-450b-5p as a highly enriched miRNA in E-EVs. Treatment with either E-EVs or miR-450b-5p mimics significantly protected RGCs against RIR-induced injury. Mechanistic investigations identified acyl-coenzyme A (CoA) synthetase long-chain family member 4 (ACSL4) as a direct target of miR-450b-5p.
Conclusion: Ex-4 exerts its neuroprotective effects under RIR injury by stimulating retinal VECs to secrete miR-450b-5p-enriched EVs, thereby revealing a novel endothelial-mediated neuroprotective pathway in ischemia diseases.
Keywords: exendin-4, retinal ganglion cells, ischemia reperfusion injury, retinal vascular endothelial cells, extracellular vesicles, microRNA