title: Plasma exosomes protect the myocardium from ischemia-reperfusion injury.
abstract: 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.
  
  
  OBJECTIVE
  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.
  
  
  CONCLUSIONS
  Exosomes deliver endogenous protective signals to the myocardium by a pathway involving TLR4 and classic cardioprotective HSPs.
authors.affiliation: The Hatter Cardiovascular Institute, University College London, London, United Kingdom.
authors.forename: Jose M
authors.initials: JM
authors.lastname: Vicencio
authors.affiliation: The Hatter Cardiovascular Institute, University College London, London, United Kingdom. Electronic address: d.yellon@ucl.ac.uk.
authors.forename: Derek M
authors.initials: DM
authors.lastname: Yellon
authors.affiliation: The Hatter Cardiovascular Institute, University College London, London, United Kingdom.
authors.forename: Vivek
authors.initials: V
authors.lastname: Sivaraman
authors.affiliation: The Hatter Cardiovascular Institute, University College London, London, United Kingdom.
authors.forename: Debashish
authors.initials: D
authors.lastname: Das
authors.affiliation: The Hatter Cardiovascular Institute, University College London, London, United Kingdom.
authors.forename: Claire
authors.initials: C
authors.lastname: Boi-Doku
authors.affiliation: The Hatter Cardiovascular Institute, University College London, London, United Kingdom.
authors.forename: Sapna
authors.initials: S
authors.lastname: Arjun
authors.affiliation: The Hatter Cardiovascular Institute, University College London, London, United Kingdom.
authors.forename: Ying
authors.initials: Y
authors.lastname: Zheng
authors.affiliation: Advanced Center for Chronic Diseases and Centro Estudios Moleculares de la Célula, Facultad de Ciencias Químicas y Farmacéuticas and Facultad de Medicina, Universidad de Chile, Santiago, Chile.
authors.forename: Jaime A
authors.initials: JA
authors.lastname: Riquelme
authors.affiliation: The Hatter Cardiovascular Institute, University College London, London, United Kingdom.
authors.forename: Jessica
authors.initials: J
authors.lastname: Kearney
authors.affiliation: The Hatter Cardiovascular Institute, University College London, London, United Kingdom.
authors.forename: Vikram
authors.initials: V
authors.lastname: Sharma
authors.affiliation: Department of Radiation Oncology, Klinikum rechts der Isar, Technische Universität München, München, Germany.
authors.forename: Gabriele
authors.initials: G
authors.lastname: Multhoff
authors.affiliation: The Hatter Cardiovascular Institute, University College London, London, United Kingdom.
authors.forename: Andrew R
authors.initials: AR
authors.lastname: Hall
authors.affiliation: The Hatter Cardiovascular Institute, University College London, London, United Kingdom.
authors.forename: Sean M
authors.initials: SM
authors.lastname: Davidson
mesh_terms: D000328:Adult; D000818:Animals; D055354:Exosomes / Q000378:metabolism* / Q000473:pathology; D055551:HSP27 Heat-Shock Proteins / Q000378:metabolism; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism; D064368:Healthy Volunteers; D006801:Humans; D008297:Male; D008854:Microscopy, Electron; D008875:Middle Aged; D015428:Myocardial Reperfusion Injury / Q000517:prevention & control*; D032383:Myocytes, Cardiac / Q000166:cytology; D017207:Rats, Sprague-Dawley; D060225:Tetraspanin 28 / Q000378:metabolism; D060149:Tetraspanin 30 / Q000378:metabolism
chemical_list: D055551:HSP27 Heat-Shock Proteins; D018840:HSP70 Heat-Shock Proteins; D060225:Tetraspanin 28; D060149:Tetraspanin 30
keywords: cardioprotection; exosomes; heat shock protein; ischemia-reperfusion injury; toll-like receptor