Inflammatory extracellular vesicles prompt heart dysfunction via TRL4-dependent NF-κB activation.

Details

Serval ID
serval:BIB_34FB0B3FF9EA
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
Inflammatory extracellular vesicles prompt heart dysfunction via TRL4-dependent NF-κB activation.
Journal
Theranostics
Author(s)
Biemmi V., Milano G., Ciullo A., Cervio E., Burrello J., Dei Cas M., Paroni R., Tallone T., Moccetti T., Pedrazzini G., Longnus S., Vassalli G., Barile L.
ISSN
1838-7640 (Electronic)
ISSN-L
1838-7640
Publication state
Published
Issued date
2020
Peer-reviewed
Oui
Volume
10
Number
6
Pages
2773-2790
Language
english
Notes
Publication types: Journal Article
Publication Status: epublish
Abstract
Background: After myocardial infarction, necrotic cardiomyocytes release damage-associated proteins that stimulate innate immune pathways and macrophage tissue infiltration, which drives inflammation and myocardial remodeling. Circulating inflammatory extracellular vesicles play a crucial role in the acute and chronic phases of ischemia, in terms of inflammatory progression. In this study, we hypothesize that the paracrine effect mediated by these vesicles induces direct cytotoxicity in cardiomyocytes. Thus, we examined whether reducing the generation of inflammatory vesicles within the first few hours after the ischemic event ameliorates cardiac outcome at short and long time points. Methods: Myocardial infarction was induced in rats that were previously injected intraperitoneally with a chemical inhibitor of extracellular-vesicle biogenesis. Heart global function was assessed by echocardiography performed at 7, 14 and 28 days after MI. Cardiac outcome was also evaluated by hemodynamic analysis at sacrifice. Cytotoxic effects of circulating EV were evaluated ex-vivo in a Langendorff, system by measuring the level of cardiac troponin I (cTnI) in the perfusate. Mechanisms undergoing cytotoxic effects of EV derived from pro-inflammatory macrophages (M1) were studied in-vitro in primary rat neonatal cardiomyocytes. Results: Inflammatory response following myocardial infarction dramatically increased the number of circulating extracellular vesicles carrying alarmins such as IL-1α, IL-1β and Rantes. Reducing the boost in inflammatory vesicles during the acute phase of ischemia resulted in preserved left ventricular ejection fraction in vivo. Hemodynamic analysis confirmed functional recovery by displaying higher velocity of left ventricular relaxation and improved contractility. When added to the perfusate of isolated hearts, post-infarction circulating vesicles induced significantly more cell death in adult cardiomyocytes, as assessed by cTnI release, comparing to circulating vesicles isolated from healthy (non-infarcted) rats. In vitro inflammatory extracellular vesicles induce cell death by driving nuclear translocation of NF-κB into nuclei of cardiomyocytes. Conclusion: Our data suggest that targeting circulating extracellular vesicles during the acute phase of myocardial infarction may offer an effective therapeutic approach to preserve function of ischemic heart.
Keywords
TLR4 axis, inflammatory extracellular vesicles, macrophages, myocardial infarction
Pubmed
Web of science
Open Access
Yes
Create date
01/04/2020 21:05
Last modification date
02/02/2021 7:26
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