A fibroblast‐specific miRNA functional cluster in remote exosomes aggravates myocardial ischaemia/reperfusion injury via the Rap1b/ERK1/2 axis

作者：Rui Zhang, Mingjue Li, Jiarui Jin, Xuemei Fu, Hailin Zhu, Xiaoxia Huang, Mingyuan He, Zhihong Li, Rongzhan Lin, Hairuo Lin, Tong Zhang, Wangjun Liao, Jianping Bin, Qiancheng Wang, Cankun Zheng, Yulin Liao · 发表于：British Journal of Pharmacology · 年份：2025 · DOI：10.1111/bph.70249 · 被引用次数：2 · 研究领域：Extracellular vesicles in disease、MicroRNA in disease regulation、Cardiac Fibrosis and Remodeling

BACKGROUND AND PURPOSE: Communication between various cardiac cells by paracrine factors and exosomes has an important role in myocardial ischaemia/reperfusion (I/R) injury. It remains unclear whether exosomes derived from healthy cardiac fibroblasts affect I/R injury and, if so, what are the underlying mechanisms? EXPERIMENTAL APPROACH: Cardiac fibroblasts were isolated from neonatal rats, adult rats and adult rats subjected to I/R. Their exosomes were designated as follows: neonatal cardiac fibroblasts (N-Exo), adult rat cardiac fibroblasts (A-Exo) and cardiac fibroblasts in a remote non-ischaemic area (R-Exo). Apoptosis of cardiomyocytes and the role of a cluster of microRNAs from exosomes in I/R injury were investigated. KEY RESULTS: N-Exo, A-Exo and R-Exo were taken up by ischaemic cardiomyocytes through clathrin heavy chain (Cltc)-mediated endocytosis, enhancing cardiomyocyte apoptosis and increasing myocardial infarct size in rats and mice. Inhibiting Cltc-mediated endocytosis with chlorpromazine reduced the pro-apoptotic effects of N-Exo in neonatal rat cardiomyocytes under anoxia/reoxygenation. A functional cluster of miRNAs (miR-9a-5p, miR-92b-3p, miR-181a-5p, miR-494-3p and miR-708-5p) from exosomes was identified and promoted cardiomyocyte apoptosis via a common gene, Rap1b. R-Exo downregulated cardiac Rap1b and Bcl2 in I/R rats. Mimics of these miRNAs reduced luciferase activity of the Rap1b gene and were blocked by site-directed mutagenesis of the Rap1b gene at ...