Intercellular mitochondrial component transfer triggers ischemic cardiac fibrosis.

Area of Science:

• Cardiovascular Biology
• Cellular Communication
• Extracellular Vesicles

Background:

• Myocardial fibrosis is a major cause of sudden cardiac death.
• Intercellular communication mechanisms driving post-ischemia/reperfusion (MI/R) fibrosis are unclear.
• Small extracellular vesicles (sEVs) are implicated in cell-to-cell signaling.

Purpose of the Study:

• To investigate the role of cardiomyocyte-derived sEVs (Myo-sEVs) in mediating cardiac fibrosis after MI/R injury.
• To identify molecular components within Myo-sEVs responsible for initiating fibrosis.
• To explore Ambra1 as a potential marker and therapeutic target in cardiac fibrosis.

Main Methods:

• Establishment of in vivo and in vitro MI/R models.
• Analysis of Myo-sEVs contents and their effects on fibroblasts.
• Bioinformatics screening and experimental validation of Ambra1.
• Investigation of secretory autophagy in Myo-sEV release.
• Assessment of Ambra1's role in fibroblast activation via the cGAS-STING pathway.
• Evaluation of cardiac-specific Ambra1 downregulation effects on fibrosis.

Main Results:

• Myo-sEVs from MI/R hearts carry mitochondrial components that induce myocardial fibrosis.
• Ambra1 is identified as a critical component and potential marker of Myo-sEVs.
• Ambra1+ -Myo-sEVs are released via secretory autophagy and activate fibroblast cGAS-STING signaling.
• Downregulation of Ambra1 inhibits Myo-sEV release and subsequent cardiac fibrosis.

Conclusions:

• Myocardial secretory autophagy mediates intercellular communication in cardiac fibrosis.
• Ambra1+ -Myo-sEVs deliver mtDNA to fibroblasts, promoting fibrosis.
• Ambra1 is a novel bioactive molecule and potential therapeutic target for cardiac remodeling.