Department of Cardiology, Beijing An Zhen Hospital, Capital Medical University, Beijing, 100029, China.
Beijing An Zhen Hospital, Capital Medical University, The Key Laboratory of Remodeling Cardiovascular Diseases, Ministry of Education; Collaborative Innovation Center for Cardiovascular Disorders, Beijing Institute of Heart Lung and Blood Vessel Disease, Beijing, 100029, China.
Theranostics. 2024 Sep 9;14(15):5926-5944. doi: 10.7150/thno.99507. eCollection 2024.
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. High-fat diet (HFD)-induced and genetic () type 2 diabetic models were utilized. Cardiomyocyte sEVs (Myo-sEVs) were isolated by ultracentrifugation. Normal cardiomyocyte-derived Myo-sEVs attenuated diabetic cardiac fibrosis and 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 and experiments demonstrated that miR-194-3p is a novel upstream molecule inhibiting TGFβR2 expression and blocking fibroblast-myofibroblast conversion. Administration of miR-194-3p mimic or agomiR-194-3p significantly reduced diabetic cardiac fibrosis and , and attenuated diabetic cardiomyopathy. Our study demonstrates for the first time that cardiomyocyte-derived miR194-3p inhibits TGFβ-mediated fibroblast-to-myofibroblast conversion, acting as an internal break against cardiac fibrosis. Diabetic downregulation of sEV-mediated miR-194-3p delivery from cardiomyocytes to fibroblasts contributes to diabetic cardiac fibrosis and diabetic cardiomyopathy. Pharmacological or genetic restoration of this system may be a novel therapy against diabetic cardiomyopathy.
糖尿病性心肌病是糖尿病心血管并发症的主要类型之一，其中纤维化起着关键的发病作用。然而，糖尿病如何触发心脏中的心肌纤维化的确切机制仍不清楚。细胞外小泡（sEVs）在细胞通讯中起着重要作用。然而，糖尿病是否以及如何可能改变 sEVs 介导的心肌细胞-成纤维细胞通讯，促进糖尿病性心肌纤维化并导致糖尿病性心肌病，尚未得到研究。使用高脂肪饮食（HFD）诱导和遗传（）2 型糖尿病模型。通过超速离心分离心肌细胞 sEVs（Myo-sEVs）。正常心肌细胞衍生的 Myo-sEVs 减轻了糖尿病性心肌纤维化和改善了心脏舒张功能。相比之下，糖尿病心肌细胞衍生的 Myo-sEVs 显著加重了糖尿病性心肌纤维化并恶化了舒张功能。无偏 miRNA 筛选分析显示，糖尿病 Myo-sEVs 中的 miR-194-3p 显著减少。进一步的和实验表明，miR-194-3p 是一种新的上游分子，可抑制 TGFβR2 表达并阻断成纤维细胞-肌成纤维细胞转化。给予 miR-194-3p 模拟物或 agomiR-194-3p 可显著减少糖尿病性心肌纤维化和，并减轻糖尿病性心肌病。我们的研究首次表明，心肌细胞衍生的 miR194-3p 抑制 TGFβ 介导的成纤维细胞向肌成纤维细胞转化，作为心脏纤维化的内在阻断物。糖尿病下调心肌细胞向成纤维细胞传递 sEV 介导的 miR-194-3p 表达，导致糖尿病性心肌纤维化和糖尿病性心肌病。该系统的药理学或遗传恢复可能是治疗糖尿病性心肌病的一种新方法。
