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Open AccessArticle

Calcium Ionophore-Induced Extracellular Vesicles Mediate Cytoprotection against Simulated Ischemia/Reperfusion Injury in Cardiomyocyte-Derived Cell Lines by Inducing Heme Oxygenase 1

1
National Institute of Chemistry, SI-1000 Ljubljana, Slovenia
2
Graduate School of Biomedicine, Faculty of Medicine, University of Ljubljana, SI-1000 Ljubljana, Slovenia
3
Department of Pharmacology and Pharmacotherapy, Semmelweis University, 1085 Budapest, Hungary
4
Centre of Excelence EN-FIST, SI-1000 Ljubljana, Slovenia
5
Pharmahungary Group, 6722 Szeged, Hungary
6
Institute of Experimental Medicine, ELRN, 1083 Budapest, Hungary
7
Centre of Experimental Medicine, Institute for Heart Research, Slovak Academy of Sciences, 84104 Bratislava, Slovakia
8
Institute of Physiology, Faculty of Medicine, Comenius University in Bratislava, 81372 Bratislava, Slovakia
*
Authors to whom correspondence should be addressed.
These authors contributed equally to this work.
Int. J. Mol. Sci. 2020, 21(20), 7687; https://doi.org/10.3390/ijms21207687
Received: 10 July 2020 / Revised: 6 October 2020 / Accepted: 14 October 2020 / Published: 16 October 2020
(This article belongs to the Section Molecular Pathology, Diagnostics, and Therapeutics)
Cardioprotection against ischemia/reperfusion injury is still an unmet clinical need. The transient activation of Toll-like receptors (TLRs) has been implicated in cardioprotection, which may be achieved by treatment with blood-derived extracellular vesicles (EVs). However, since the isolation of EVs from blood takes considerable effort, the aim of our study was to establish a cellular model from which cardioprotective EVs can be isolated in a well-reproducible manner. EV release was induced in HEK293 cells with calcium ionophore A23187. EVs were characterized and cytoprotection was assessed in H9c2 and AC16 cell lines. Cardioprotection afforded by EVs and its mechanism were investigated after 16 h simulated ischemia and 2 h reperfusion. The induction of HEK293 cells by calcium ionophore resulted in the release of heterogenous populations of EVs. In H9c2 and AC16 cells, stressEVs induced the downstream signaling of TLR4 and heme oxygenase 1 (HO-1) expression in H9c2 cells. StressEVs decreased necrosis due to simulated ischemia/reperfusion injury in H9c2 and AC16 cells, which was independent of TLR4 induction, but not that of HO-1. Calcium ionophore-induced EVs exert cytoprotection by inducing HO-1 in a TLR4-independent manner. View Full-Text
Keywords: extracellular vesicles; TLR4; HO-1; cardioprotection; ischemia/reperfusion injury extracellular vesicles; TLR4; HO-1; cardioprotection; ischemia/reperfusion injury
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Pečan, P.; Hambalkó, S.; Ha, V.T.; Nagy, C.T.; Pelyhe, C.; Lainšček, D.; Kenyeres, B.; Brenner, G.B.; Görbe, A.; Kittel, Á.; Barteková, M.; Ferdinandy, P.; Manček-Keber, M.; Giricz, Z. Calcium Ionophore-Induced Extracellular Vesicles Mediate Cytoprotection against Simulated Ischemia/Reperfusion Injury in Cardiomyocyte-Derived Cell Lines by Inducing Heme Oxygenase 1. Int. J. Mol. Sci. 2020, 21, 7687.

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