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Published on: March 15, 2024
Engineered ZFP36-overexpressing AC16 cell-derived extracellular vesicles attenuate ferroptosis-related endothelial
Demin Li1, Yachen Hou1, Yang Lu1
1Department of Cardiology, First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, 450052, China; State Key Laboratory of Metabolic Dysregulation & Prevention and Treatment of Esophageal Cancer, Tianjian Laboratory of Advanced Biomedical Sciences, Zhengzhou, Henan, 450001, China; Key Laboratory of Cardiac Injury and Repairof Henan Province, Zhengzhou, Henan, 450052, China; Henan Province Clinical Research Center for Cardiovascular Diseases, Zhengzhou, Henan, 450052, China; Henan Province Academy of Cardiovascular Disease Prevention and Treatment, Henan, 450052, China.
Abstract:
Myocardial infarction (MI) is associated with persistent myocardial injury and vascular dysfunction despite advances in reperfusion therapy. Delayed endothelial recovery, inflammation, and vascular remodeling remain important challenges during post-MI repair and vascular intervention. Here, we investigated whether extracellular vesicles (EVs) derived from ZFP36-overexpressing AC16 cells could attenuate ferroptosis-related endothelial injury, improve cardiac function after MI, and be integrated into a bioactive NiTi surface for vascular repair. Bioinformatic screening identified ZFP36 as an MI-associated candidate linked to ferroptosis-related processes; increased expression was subsequently observed in the mouse MI model. ZFP36-overexpressing AC16 cells were generated, and the released EVs were designated ZFP36OE-EV. In RSL3-treated HUVECs, ZFP36OE-EV improved cell viability, reduced oxidative stress, preserved mitochondrial membrane potential, and partially restored ferroptosis-related molecular changes. In a mouse MI model, intramyocardial delivery of ZFP36OE-EV improved cardiac function and reduced myocardial fibrosis. To explore the use of the same engineered EV preparation for vascular interface functionalization, ZFP36OE-EV was immobilized onto a polydopamine/hyaluronic acid (PDA/HA)-modified NiTi surface to generate the NPH@Z-EV coating. The coating supported EV loading and gradual particle release in vitro. Under direct cell-material contact conditions, the NPH@Z-EV coating exhibited endothelial protective activity under ferroptosis-related stress. In a rat femoral artery injury model, the NPH@Z-EV coating supported vascular repair, with improved endothelial recovery, reduced local inflammatory activation, attenuated lipid peroxidation-associated vascular injury, and a VSMC marker pattern consistent with reduced phenotypic switching. These findings support further evaluation of engineered EVs as a strategy for functionalizing NiTi vascular interfaces to improve vascular healing after implantation.