Plasma Exosomes Protect the Myocardium From Ischemia-Reperfusion Injury
Author
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Vicencio, José M.
Author
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Yellon, Derek M.
Author
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Sivaraman, Vivek
Author
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Das, Debashish
Author
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Boi-Doku, Claire
Author
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Arjun, Sapna
Author
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Zheng, Ying
Author
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Riquelme, Jaime A.
Author
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Kearney, Jessica
Author
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Sharma, Vikram
Author
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Multhoff, Gabriele
Author
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Hall, Andrew R.
Author
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Davidson, Sean M.
Admission date
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2015-07-27T14:56:36Z
Available date
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2015-07-27T14:56:36Z
Publication date
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2015
Cita de ítem
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Journal of The American College of Cardiology, vol. 65, No. 15, 2015
en_US
Identifier
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0735-1097
Identifier
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https://repositorio.uchile.cl/handle/2250/132112
General note
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Artículo de publicación ISI
en_US
Abstract
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BACKGROUND Exosomes are nanometer-sized vesicles released from cells into the blood, where they can transmit
signals throughout the body. Shown to act on the heart, exosomes’ composition and the signaling pathways they activate
have not been explored. We hypothesized that endogenous plasma exosomes can communicate signals to the heart and
provide protection against ischemia and reperfusion injury.
OBJECTIVES This study sought to isolate and characterize exosomes from rats and healthy volunteers, evaluate their
cardioprotective actions, and identify the molecular mechanisms involved.
METHODS The exosome-rich fraction was isolated from the blood of adult rats and human volunteers and was analyzed
by protein marker expression, transmission electron microscopy, and nanoparticle tracking analysis. This was then used in
ex vivo, in vivo, and in vitro settings of ischemia-reperfusion, with the protective signaling pathways activated on
cardiomyocytes identified using Western blot analyses and chemical inhibitors.
RESULTS Exosomes exhibited the expected size and expressed marker proteins CD63, CD81, and heat shock protein
(HSP) 70. The exosome-rich fraction was powerfully cardioprotective in all tested models of cardiac ischemia-reperfusion
injury. We identified a pro-survival signaling pathway activated in cardiomyocytes involving toll-like receptor (TLR) 4 and
various kinases, leading to activation of the cardioprotective HSP27. Cardioprotection was prevented by a neutralizing
antibody against a conserved HSP70 epitope expressed on the exosome surface and by blocking TLR4 in cardiomyocytes,
identifying the HSP70/TLR4 communication axis as a critical component in exosome-mediated cardioprotection.