Exosomes from macrophages intervened by Jiedu Yangxin decoction mediated endothelial-to-mesenchymal transition to improve myocardial fibrosis after myocardial infarction

Background and purpose: Myocardial fibrosis, a critical pathological feature in myocardial infarction (MI) associated with adverse outcomes. Endothelial-to-mesenchymal transition (EndMT) emerges as a central driver of fibrosis, regulated by macrophage polarization and exosomal MicroRNAs (miRNAs). This study elucidates the anti-fibrotic mechanism of Jiedu Yangxin Decoction (JDYX), a Traditional Chinese Medicine, investigating regulation of macrophage-derived exosomes and suppression of EndMT in post-myocardial infarction (MI) cardiac remodelling.

Experimental approach: In vivo, 8-week-old male C57BL/6J mice underwent left anterior descending (LAD) coronary artery ligation and received intragastric JDYX at different post-MI time windows. Cardiac function, fibrosis and EndMT were assessed by echocardiography, histology, Western blot and RT-qPCR. Co-staining was used to examine the association between M2 macrophages and EndMT. In vitro, endothelial cells were co-cultured with macrophage exosomes. Exosomes were characterized, and miRNA Sequencing was performed to identify miR-23b-3p.HCAECs were exposed to exosomes from THP-1 with miR-23b-3p modulation, and SMAD3 pathway was assessed by WB.

Key results: In MI mice, early JDYX intervention (0-7 days) most effectively preserved cardiac function, while reducing fibrosis. JDYX attenuated EndMT, reversing mesenchymal marker upregulation and endothelial marker suppression. JDYX regulated macrophage phenotype, increasing Arg-1 and IL-10, thereby alleviating EndMT. Crucially, JDYX-reprogrammed macrophage-derived exosomes improved M1 macrophage-derived exosomes-induced EndMT in vitro. miRNA-seq revealed miR-23b-3p enrichment in JDYX-exosomes. The protective effect of JDYX against EndMT was compromised when using exosomes from miR-23b-3p-knockdown macrophages.

Conclusion and implications: JDYX improves myocardial fibrosis by targeting macrophage-derived exosomal miRNAs, thereby attenuating EndMT.