Abstract 15392: Exosomal microRNA 486-5p Mediates Cardiac Angiogenesis Post Myocardial Infarction by Targeting MMP19 in Fibroblasts

Background:Neovascularization is a pivotal factor to improve cardiac performance recovery from injury induced by myocardial infarction (MI). Exosomes secreted by stem cells, due to their unique profile of contents, can promote myocardial angiogenesis; however, the exosomal cargo contributed to these effects remains unresolved.Objective:The current study was aiming to evaluate the effect and mechanisms of exosomal mir-486-5p on cardiac angiogenesis post MI.Methods and Results:The abundance of mir-486-5p was significantly elevated in exosomes from hypoxic MSCs (MSCs treated with 0.5% oxygen for 24 hours) versus Normoxic controls. Furthermore, mir-486-5p levels positively correlate with pro-angiogenic responses in cardiac tissues treated with exosomes from hypoxic MSCs. Treating infarcted myocardium with mir-486-5p over-expressed exosomes from normoxic MSCs was sufficient to recapitulate effects observed with hypoxic MSCs derived exosomes on cardiac angiogenesis. Conversely, inhibition of mir-486-5p in hypoxic MSCs derivedexosomes significantly diminished exosomal pro-angiogenic effects on myocardial tissue post MI. Mechanistically, exosomal mir-486-5p could be transferred from MSCs to cardiac fibroblast, thus suppressed the expression of MMP19, thereby reduced the cleavage of VEGFA and restored the concentration of intact VEGFA, ultimately promote angiogenesis. Finally, directly injected mir-486-5p engineered MSCs derived exosome to nonhuman primate MI model also showed a robust angiogenic capacity and cardio-protective effect without inducing malignant arrhythmia.Conclusion:The present study highlight the key role of exosomal mir-486-5p on cardiac angiogenesis via fibroblastic MMP19-VEGFA cleavage signaling and may provide novel approach to utilize mir-486-5p in maximizing angiogenesis for cardiac repair.