Eleonora Foglio1, Giovanni Puddighinu1, Pasquale Fasanaro2, Daniela D'Arcangelo3, Giulietta A Perrone4, David Mocini4, Ciro Campanella4, Luigi Coppola4, Mariantonia Logozzi5, Tommaso Azzarito5, Francesca Marzoli5, Stefano Fais5, Luisa Pieroni6, Valeria Marzano7, Antonia Germani3, Maurizio C Capogrossi3, Matteo A Russo8, Federica Limana9. 1. Department of Experimental Medicine, Sapienza University of Rome, Rome, Italy. 2. Epigenetics & Regenerative Pharmacology, IRCCS Fondazione Santa Lucia, Rome, Italy. 3. Laboratorio di Patologia Vascolare, Istituto Dermopatico dell'Immacolata, IRCCS, Rome, Italy. 4. Ospedale San Filippo Neri, Rome, Italy. 5. Department of Therapeutic Research and Medicines Evaluation, National Institute of Health, Italy. 6. Dipartimento di Medicina Sperimentale e Chirurgia, Facoltà di Medicina e Chirurgia, Università' di Roma "Tor Vergata", Italy. 7. Institute of Chemistry of Molecular Recognition, Italian National Research Council (CNR), Rome, Italy. 8. Laboratorio di Patologia Cellulare e Molecolare, San Raffaele Pisana, Istituto di Ricovero e Cura a Carattere Scientifico - IRCCS, Rome, Italy. 9. 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.
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. METHODS AND 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.
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. METHODS AND RESULTS: Early gene expression studies in 3day-infarctedmouse hearts showed that PF induces epithelial-to-mesenchymal transition (EMT) in epicardial cells. Exosomes were identified in PFs from non-infarctedpatients (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: A P Sklifasovskaya; M L Blagonravov; A Yu Ryabinina; M M Azova; V A Goryachev Journal: Bull Exp Biol Med Date: 2021-10-07 Impact factor: 0.804