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American Heart Association

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Final ID: LBMP14

Adipocyte-Derived Small Extracellular Vesicles Enriched with NNMT Inhibit Angiogenesis Post-Myocardial Infarction in Diabetes

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.
  • Ren, Hang  ( Westchina hospital , Chengdu , China )
  • Cao, Liwen  ( West China Hospital, SCU , Chengdu , China )
  • Zhao, Zhenkun  ( West China Hospital, SCU , Chengdu , China )
  • Huang, Ying  ( West China Hospital, SCU , Chengdu , China )
  • Pan, Zhongjing  ( West China Hospital, SCU , Chengdu , China )
  • Cheng, Liangfen  ( West China Hospital, SCU , Chengdu , China )
  • Gan, Lu  ( West China Hospital, SCU , Chengdu , China )
  • Author Disclosures:
    hang ren: DO NOT have relevant financial relationships | Liwen Cao: No Answer | Zhenkun Zhao: No Answer | Ying Huang: No Answer | Zhongjing Pan: No Answer | Liangfen Cheng: No Answer | Lu Gan: DO NOT have relevant financial relationships
Meeting Info:

Scientific Sessions 2025

2025

New Orleans, Louisiana

Session Info:

From Chromatin to Cytokines: Mechanistic Insights into Heart Failure

Sunday, 11/09/2025 , 03:15PM - 04:30PM

Moderated Digital Poster Session

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