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Preclinical studies and opioids: role in crisis management in the United States Authors
X Loyer, I Zlatanova, C Devue, M Yin, K-Y Howangyin, et al.
Lab
Paris Cardiovascular Research Center, INSERM UMR-S 970, France
Journal
Circulation Research
Abstract
Rationale: A rapid and massive influx of inflammatory cells occurs into ischemic area following myocardial infarction, resulting in local release of cytokines and growth factors. Yet, the mechanisms regulating their production are not fully explored. The release of extracellular vesicles (EV) in the interstitial space curbs important biological functions, including inflammation, and influences the development of cardiovascular diseases. So far, there is no evidence for in situ release of cardiac EVs following myocardial infarction.
Objective: The present study tested the hypothesis that local EV generation in the infarcted heart coordinates cardiac inflammation following myocardial infarction.
Methods and Results: Coronary artery ligation in mice transiently increases EV levels in the left ventricle when compared to sham animals. EVs from infarcted hearts were characterized as large vesicles (252±18nm) expressing cardiomyocyte and endothelial markers, and small EVs (118±4nm) harboring exosomal markers such as CD63 and CD9. Cardiac large EVs generated after myocardial infarction, but not small EVs or sham EVs, increased the release of interleukin-6, chemokines CCL2, CCL7 from FACS-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 myocardial infarction 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.