Cardiomyocyte-derived small extracellular vesicle: a new mechanism driving diabetic cardiac fibrosis and cardiomyopathy

作者：Yu Li, Yunhui Du, Jing Yang, Xiuhuan Chen, Xinxin Li, Yanru Duan, Yanwen Qin, Huirong Liu, Xinliang Ma, Shaoping Nie, Huina Zhang · 发表于：Theranostics · 年份：2024 · DOI：10.7150/thno.99507 · 被引用次数：14 · 研究领域：Cardiovascular Effects of Exercise、Cardiovascular Disease and Adiposity、Cardiovascular Function and Risk Factors

Rationale: Diabetic cardiomyopathy is one of the major diabetic cardiovascular complications in which fibrosis plays a critical pathogenetic role.However, the precise mechanisms by which diabetes triggers cardiac fibrosis in the heart remain elusive.Small extracellular vesicles (sEVs) play an important role in the cellular communication.Nevertheless, whether and how diabetes may adversely alter sEVs-mediated cardiomyocyte-fibroblast communication, promoting diabetic cardiac fibrosis and contributing to diabetic cardiomyopathy, has not been previously investigated.Methods and results: High-fat diet (HFD)-induced and genetic (db/db) type 2 diabetic models were utilized.Cardiomyocyte sEVs (Myo-sEVs) were isolated by ultracentrifugation.Normal cardiomyocyte-derived Myo-sEVs attenuated diabetic cardiac fibrosis in vitro and in vivo and improved cardiac diastolic function.In contrast, diabetic cardiomyocyte-derived Myo-sEVs significantly exacerbated diabetic cardiac fibrosis and worsened diastolic function.Unbiased miRNA screening analysis revealed that miR-194-3p was significantly reduced in diabetic Myo-sEVs.Additional in vitro and in vivo experiments demonstrated that miR-194-3p is a novel upstream molecule inhibiting TGFR2 expression and blocking fibroblast-myofibroblast conversion.Administration of miR-194-3p mimic or agomiR-194-3p significantly reduced diabetic cardiac fibrosis in vitro and in vivo, and attenuated diabetic cardiomyopathy. Conclusion:Our study demonstrates for...