Yanan Sun, Ruyi Zhai, Qilian Sheng, Yue Ying, Ye Lin Kwan, Xintong Fan, Huan Xu, Xiangmei Kong
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引用次数: 0
Abstract
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.
期刊介绍：
The International Journal of Nanomedicine is a globally recognized journal that focuses on the applications of nanotechnology in the biomedical field. It is a peer-reviewed and open-access publication that covers diverse aspects of this rapidly evolving research area.
With its strong emphasis on the clinical potential of nanoparticles in disease diagnostics, prevention, and treatment, the journal aims to showcase cutting-edge research and development in the field.
Starting from now, the International Journal of Nanomedicine will not accept meta-analyses for publication.
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