EPCs-derived exosomal miR-7116-3p alleviate high glucose-induced endothelial cell dysfunction by targeting Orai1-IGFBP3 complexes

INTRODUCTION: Diabetic vascular complications are predominantly caused by high glucose (HG)-induced endothelial dysfunction. Exosomes derived from endothelial progenitor cells (EPCs-EXOs) have shown therapeutic potential by modulating cellular functions through the delivery of bioactive cargos, particularly microRNAs (miRNAs). This study examines the role of EPCs-EXOs and their miRNA cargo in mitigating HG-induced endothelial dysfunction by targeting the Orai1-insulin-like growth factor-binding protein 3 (IGFBP3) signaling axis, a critical mediator of store-operated calcium entry (SOCE) and vascular pathology in diabetes. RESEARCH DESIGN AND METHODS: Human coronary artery endothelial cells (HCAECs) were cultured under HG (25 mM) or normal glucose (5.6 mM) conditions to model endothelial dysfunction. Cellular proliferation, apoptosis, and migration were evaluated through functional assays. EPCs-EXOs were isolated from mouse bone marrow-derived EPCs and characterized via nanoparticle tracking analysis, transmission electron microscopy. A type 2 diabetic mouse model was established using streptozotocin, and atherosclerotic plaque formation was quantified by Oil Red O staining. miRNA profiling identified miR-7116-3p as a potential regulator. HCAECs and mice with diabetes were treated with EPCs-EXOs, and miR-7116-3p mimics or inhibitors were employed to evaluate the specific effects on Orai1 and IGFBP3 expression and endothelial function. RESULTS: EPCs-EXOs significantly attenuated HG-induced abnormalities in HCAECs proliferation, apoptosis, and migration, and reduced atherosclerotic plaque formation in mice with diabetes. HG conditions upregulated Orai1 and IGFBP3 expression and promoted SOCE activity, whereas EPCs-EXOs suppressed these responses. Overexpression of Orai1 or IGFBP3 abolished the protective effects of EPCs-EXOs, underscoring their essential role. miRNA profiling identified miR-7116-3p within EPCs-EXOs as a key regulator that directly targets Orai1 and IGFBP3 messenger RNAs. CONCLUSION: EPCs-EXOs alleviate HG-induced endothelial dysfunction by suppressing the Orai1-IGFBP3 signaling axis, with miR-7116-3p acting as a pivotal regulator of these targets. These findings reveal a novel mechanism and support the therapeutic potential of miR-7116-3p-enriched EPCs-EXOs for the treatment of diabetic cardiovascular diseases.