Overexpression of OTUD5 in IPSCs-derived extracellular vesicles promotes angiogenesis after myocardial infarction by inhibiting endothelial cell ferroptosis.

Abstract

BACKGROUND AND AIM: Endothelial cell ferroptosis can occur under oxidative stress conditions, thereby significantly impairing their function and hindering heart repair. Reports have demonstrated the considerable potential of ovarian tumor domain-containing protein 5 (OTUD5) in regulating ferroptosis. However, researchers have not clearly determined whether OTUD5 can inhibit endothelial cell ferroptosis following myocardial infarction (MI). METHODS AND RESULTS: Human induced pluripotent stem cells (IPSCs) were transfected with OTUD5 plasmids to collect IPSCs-derived extracellular vesicles (EVs) highly expressing OTUD5 (IPSCs-EVs). IPSCs-EVs with or without high OTUD5 expression were injected into the myocardium of mouse hearts after MI surgery. Mouse heart function at 7, 14, and 28 days after MI operation was assessed by echocardiography analysis. An reactive oxygen species (ROS) detection assay, an MDA assay, and an Felevel and iron assay were used to detect endothelial cell ferroptosis. A tube formation assay was used to determine the angiogenesis ability of endothelial cells. We discovered that the overexpression of OTUD5 in IPSCs-EVs significantly improved cardiac function and reduced cardiac remodeling by promoting angiogenesis in murine MI models. We observed that OTUD5 reduced intracellular ROS and lipid peroxide accumulation, restored GPX4 expression, and suppressed ACLS4 expression in endothelial cells. This process inhibited endothelial cell ferroptosis and preserved the proangiogenic capacity of these cells under hypoxic conditions. Further analysis revealed that the NF-κB/p65 signaling pathway was responsible for the OTUD5-induced antiferroptotic effects observed in endothelial cells. CONCLUSIONS: These findings suggest that OTUD5 modulation may serve as a promising therapeutic strategy for cardiac protection in ischemic heart diseases.