title: Exosomal clusterin, identified in the pericardial fluid, improves myocardial performance following MI through epicardial activation, enhanced arteriogenesis and reduced apoptosis.
abstract: BACKGROUND
  We recently demonstrated that epicardial progenitor cells participate in the regenerative response to myocardial infarction (MI) and factors released in the pericardial fluid (PF) may play a key role in this process. Exosomes are secreted nanovesicles of endocytic origin, identified in most body fluids, which may contain molecules able to modulate a variety of cell functions. Here, we investigated whether exosomes are present in the PF and their potential role in cardiac repair.
  
  
  RESULTS
  Early gene expression studies in 3day-infarcted mouse hearts showed that PF induces epithelial-to-mesenchymal transition (EMT) in epicardial cells. Exosomes were identified in PFs from non-infarcted patients (PFC) and patients with acute MI (PFMI). A shotgun proteomics analysis identified clusterin in exosomes isolated from PFMI but not from PFC. Notably, clusterin has a protective effect on cardiomyocytes after acute MI in vivo and is an important mediator of TGFβ-induced. Clusterin addition to the pericardial sac determined an increase in epicardial cells expressing the EMT marker α-SMA and, interestingly, an increase in the number of epicardial cells ckit(+)/α-SMA(+), 7days following MI. Importantly, clusterin treatment enhanced arteriolar length density and lowered apoptotic rates in the peri-infarct area. Hemodynamic studies demonstrated an improvement in cardiac function in clusterin-treated compared to untreated infarcted hearts.
  
  
  CONCLUSIONS
  Exosomes are present and detectable in the PFs. Clusterin was identified in PFMI-exosomes and might account for an improvement in myocardial performance following MI through a framework including EMT-mediated epicardial activation, arteriogenesis and reduced cardiomyocyte apoptosis.
authors.affiliation: Department of Experimental Medicine, Sapienza University of Rome, Rome, Italy.
authors.forename: Eleonora
authors.initials: E
authors.lastname: Foglio
authors.affiliation: Department of Experimental Medicine, Sapienza University of Rome, Rome, Italy.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Puddighinu
authors.affiliation: Epigenetics & Regenerative Pharmacology, IRCCS Fondazione Santa Lucia, Rome, Italy.
authors.forename: Pasquale
authors.initials: P
authors.lastname: Fasanaro
authors.affiliation: Laboratorio di Patologia Vascolare, Istituto Dermopatico dell'Immacolata, IRCCS, Rome, Italy.
authors.forename: Daniela
authors.initials: D
authors.lastname: D'Arcangelo
authors.affiliation: Ospedale San Filippo Neri, Rome, Italy.
authors.forename: Giulietta A
authors.initials: GA
authors.lastname: Perrone
authors.affiliation: Ospedale San Filippo Neri, Rome, Italy.
authors.forename: David
authors.initials: D
authors.lastname: Mocini
authors.affiliation: Ospedale San Filippo Neri, Rome, Italy.
authors.forename: Ciro
authors.initials: C
authors.lastname: Campanella
authors.affiliation: Ospedale San Filippo Neri, Rome, Italy.
authors.forename: Luigi
authors.initials: L
authors.lastname: Coppola
authors.affiliation: Department of Therapeutic Research and Medicines Evaluation, National Institute of Health, Italy.
authors.forename: Mariantonia
authors.initials: M
authors.lastname: Logozzi
authors.affiliation: Department of Therapeutic Research and Medicines Evaluation, National Institute of Health, Italy.
authors.forename: Tommaso
authors.initials: T
authors.lastname: Azzarito
authors.affiliation: Department of Therapeutic Research and Medicines Evaluation, National Institute of Health, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Marzoli
authors.affiliation: Department of Therapeutic Research and Medicines Evaluation, National Institute of Health, Italy.
authors.forename: Stefano
authors.initials: S
authors.lastname: Fais
authors.affiliation: Dipartimento di Medicina Sperimentale e Chirurgia, Facoltà di Medicina e Chirurgia, Università' di Roma "Tor Vergata", Italy.
authors.forename: Luisa
authors.initials: L
authors.lastname: Pieroni
authors.affiliation: Institute of Chemistry of Molecular Recognition, Italian National Research Council (CNR), Rome, Italy.
authors.forename: Valeria
authors.initials: V
authors.lastname: Marzano
authors.affiliation: Laboratorio di Patologia Vascolare, Istituto Dermopatico dell'Immacolata, IRCCS, Rome, Italy.
authors.forename: Antonia
authors.initials: A
authors.lastname: Germani
authors.affiliation: Laboratorio di Patologia Vascolare, Istituto Dermopatico dell'Immacolata, IRCCS, Rome, Italy.
authors.forename: Maurizio C
authors.initials: MC
authors.lastname: Capogrossi
authors.affiliation: Laboratorio di Patologia Cellulare e Molecolare, San Raffaele Pisana, Istituto di Ricovero e Cura a Carattere Scientifico - IRCCS, Rome, Italy.
authors.forename: Matteo A
authors.initials: MA
authors.lastname: Russo
authors.affiliation: Laboratorio di Patologia Cellulare e Molecolare, San Raffaele Pisana, Istituto di Ricovero e Cura a Carattere Scientifico - IRCCS, Rome, Italy. Electronic address: fe_limana@hotmail.com.
authors.forename: Federica
authors.initials: F
authors.lastname: Limana
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D017209:Apoptosis / Q000502:physiology; D015415:Biomarkers / Q000032:analysis / Q000378:metabolism; D051152:Clusterin / Q000032:analysis / Q000378:metabolism*; D003331:Coronary Vessels / Q000737:chemistry / Q000378:metabolism*; D055354:Exosomes / Q000737:chemistry / Q000378:metabolism*; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D009203:Myocardial Infarction / Q000175:diagnosis / Q000378:metabolism*; D009206:Myocardium / Q000737:chemistry / Q000378:metabolism / Q000473:pathology; D000069236:Pericardial Fluid / Q000737:chemistry / Q000378:metabolism*; D010496:Pericardium / Q000737:chemistry / Q000378:metabolism* / Q000473:pathology
chemical_list: D015415:Biomarkers; C495242:CLU protein, human; D051152:Clusterin
keywords: Cardiac repair; Clusterin; EMT; Epicardial cells; Molecular rehabilitation