Abstract Body (Do not enter title and authors here): Background: Diabetes exacerbates post-myocardial infarction (MI) injury, partly by inhibiting angiogenesis through incompletely understood mechanisms. Diabetic adipocyte-derived small extracellular vesicles (Adipo-sEV) contribute to ischemic injury, but their specific role in impairing post-MI angiogenesis remains unclear. This study investigated the pathological communication mediated by diabetic Adipo-sEV between adipocytes and cardiac microvascular endothelial cells (CMEC), focusing on their role in post-MI angiogenesis inhibition.
Methods: Type 2 diabetes was induced in mice via 12-week high-fat diet (HFD). Diabetic Adipo-sEV were injected intramyocardially post-MI in non-diabetic mice. Proteomics (bioinformatics, immuno-EM and WB) identified differential cargo NNMT. Adipocyte-specific Rab27a KO (inhibits sEV biogenesis) and Nnmt KO mice was used to assess the roles of adipo-sEV/NNMT in CMEC function. Mice sacrificed 4 weeks post-MI; cardiac function, fibrosis, vascular density (CD31+), and hypoxia (Hypoxyprobe+) in border zone evaluated. In vitro, CMEC migration (wound healing) and tube formation (Matrigel) assessed under High glucose and high lipid challenges plus various adipo-sEV.
Results: Intramyocardial administration of diabetic Adipo-sEVs into non-diabetic hearts post-MI significantly suppressed angiogenesis. Compared to hearts receiving non-diabetic adipo-sEVs, this resulted in impaired cardiac function, larger infarct size, reduced vascular density, and increased hypoxia within the border zone. Conversely, diabetic mice with adipocyte-specific Rab27a knockout (reducing sEV release) exhibited significantly improved post-MI angiogenesis. Mechanistically, NNMT was significantly enriched within diabetic Adipo-sEV. Critically, administration of either NNMT-depleted diabetic Adipo-sEVs or the use of diabetic mice with adipocyte-specific Nnmt knockout significantly alleviated post-MI angiogenesis inhibition and cardiac injury compared to administration of intact diabetic adipo-sEVs or wild-type controls. In vitro, diabetic Adipo-sEV suppressed CMEC migration and tube formation; this inhibitory effect was significantly rescued by NNMT-depleted diabetic Adipo-sEV.
Conclusion: NNMT enrichment in diabetic Adipo-sEV suppresses CMEC migration, angiogenesis, and exacerbates post-MI pathological remodeling, identifying a novel mechanism. Targeting NNMT-mediated adipocyte-CMEC crosstalk is a potential therapeutic strategy for diabetic post-MI injury.