Intercellular mitochondrial component transfer triggers ischemic cardiac fibrosis

Myocardial fibrosis is the villain of sudden cardiac death. Myocardial ischemia/reperfusion (MI/R) injury induces cardiomyocyte damage or even death, which in turn stimulates fibroblast activation and fibrosis, but the intercellular communication mechanism remains unknown. Recent studies have shown that small extracellular vesicles (sEVs) significantly contribute to intercellular communication. Whether and how sEV might mediate post-MI/R cardiomyocyte/fibroblasts communication remain unknown. Here, in vivo and in vitro MI/R models were established. We demonstrate that sEVs derived from cardiomyocyte (Myo-sEVs) carry mitochondrial components, which enter fibroblasts to initiate myocardial fibrosis. Based on bioinformatics screening and experimental verification, the activating molecule in Beclin1-regulated autophagy protein 1 (autophagy/beclin-1 regulator 1, Ambra1) was found to be a critical component of these sEV and might be a new marker for Myo-sEVs. Interestingly, release of Ambra1'- Myo-sEVs was caused by secretory rather than canonical autophagy after MI/R injury and thereby escaped degradation. In ischemic and peripheral areas, Ambra1'-Myo-sEVs were internalized by fibrob-lasts, and the delivered mtDNA components to activate the fibroblast cyclic GMP-AMP synthase (cGAS)stimulator of interferon genes (STING) pathway to promote fibroblast activation and proliferation. In addition, our data show that Ambra1 is expressed on the EV surface and cardiac-specific Ambra1 down regulation inhibits the Ambra1'-Myo-sEVs release and fibroblast uptake, effectively inhibiting ischemic myocardial fibrosis. This finding newly provides the evidence that myocardial secretory autophagy plays a role in intercellular communication during cardiac fibrosis. Ambra1 is a newly characterized molecule with bioactivity and might be a marker for Myo-sEVs, providing new therapeutic targets for cardiac remodeling.(c) 2023 Science China Press. Published by Elsevier B.V. and Science China Press. All rights reserved.

Automated summary

Myocardial fibrosis is a major cause of sudden cardiac death. It has been discovered that small extracellular vesicles (sEVs) released by cardiomyocytes carry mitochondrial components and can enter fibroblasts, initiating the process of myocardial fibrosis. The study also found that Ambra1 is a critical component of these sEVs and downregulation of cardiac-specific Ambra1 effectively inhibits the occurrence of myocardial fibrosis.