Intra-Cardiac Release of Extracellular Vesicles Shapes Inflammation Following Myocardial Infarction

Abstract

Rationale:A rapid and massive influx of inflammatory cells occurs into ischemic area after myocardial infarction (MI), resulting in local release of cytokines and growth factors. Yet, the mechanisms regulating their production are not fully explored. The release of extracellular vesicles (EVs) in the interstitial space curbs important biological functions, including inflammation, and influences the development of cardiovascular diseases. To date, there is no evidence for in situ release of cardiac EVs after MI.Objective:The present study tested the hypothesis that local EV generation in the infarcted heart coordinates cardiac inflammation after MI.Methods and Results:Coronary artery ligation in mice transiently increases EV levels in the left ventricle when compared with sham animals. EVs from infarcted hearts were characterized as large vesicles (252±18 nm) expressing cardiomyocyte and endothelial markers and small EVs (118±4 nm) harboring exosomal markers, such as CD (cluster of differentiation) 63 and CD9. Cardiac large EVs generated after MI, but not small EVs or sham EVs, increased the release of IL (interleukin)-6, CCL (chemokine ligand) 2, and CCL7 from fluorescence-activated cell–sorted Ly6C+ cardiac monocytes. EVs of similar diameter were also isolated from fragments of interventricular septum obtained from patients undergoing aortic valve replacement, thus supporting the clinical relevance of our findings in mice.Conclusions:The present study demonstrates that acute MI transiently increases the generation of cardiac EVs characterized as both exosomes and microvesicles, originating mainly from cardiomyocytes and endothelial cells. EVs accumulating in the ischemic myocardium are rapidly taken up by infiltrating monocytes and regulate local inflammatory responses.

The role of microvesicles and its active molecules in regulating cellular biology

“…In ischaemic encephalopathy, MVs can promote the progression of ischaemic encephalopathy . MVs can induce target cell injury by reducing cell viability, promoting cell dysfunction and inflammation after interaction with cardiomyocytes, endothelial cells and nerve cells. The investigators considered that the damage of MVs may be correlated to the bad state of the source cells.…”

Extracellular vesicles, news about their role in immune cells: physiology, pathology and diseases

“…Extracellular vesicles from human liver stem cells reduce injury in an ex-vivo normo-thermic hypoxic rat liver perfusion model [33]. Upon heart infarction, stem cell therapy, induced by myocardial or myocyte progenitor cells, is mediated by factors affecting T cell proliferation and function [35,36]. Upon heart infarction, stem cell therapy, induced by myocardial or myocyte progenitor cells, is mediated by factors affecting T cell proliferation and function [35,36].…”

“…In the lung, anti-inflammatory EVs addressed to alveolar macrophages result in the protection of epithelial cells [34]. Upon heart infarction, stem cell therapy, induced by myocardial or myocyte progenitor cells, is mediated by factors affecting T cell proliferation and function [35,36]. Among the intermediate mechanisms activated within T cells are the up-and down-regulation of several intracellular pathways.…”

“…Among the intermediate mechanisms activated within T cells are the up-and down-regulation of several intracellular pathways. The success of the progenitor cells employed depends on their strong capacity for immunosuppression [34][35][36].…”

Examining the Paracrine Effects of Exosomes in Cardiovascular Disease and Repair

“…EVs also compose a critical component of intercellular signaling by transporting molecular cargo from donor cells to recipient cells, thereby modulating gene expression and influencing the phenotype of the recipient cell . Most studies have documented this intercellular communication in vitro, but emerging evidence suggests it also occurs in vivo . In this review, we focus on the role of exosomes, a subset of EVs, as mediators of intercellular signaling in the heart.…”