Exosomal clusterin, identified in the pericardial fluid, improves myocardial performance following MI through epicardial activation, enhanced arteriogenesis and reduced apoptosis

Eleonora Foglio, Giovanni Puddighinu, Pasquale Fasanaro, Daniela D'Arcangelo, Giulietta A. Perrone, David Mocini, Ciro Campanella, Luigi Coppola, Mariantonia Logozzi, Tommaso Azzarito, Francesca Marzoli, Stefano Fais, Luisa Pieroni, Valeria Marzano, Antonia Germani, Maurizio C. Capogrossi, Matteo A. Russo, Federica Limana

Research output: Contribution to journalArticle

Abstract

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 3 day-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+, 7 days 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.

Original languageEnglish
Article number20664
Pages (from-to)333-347
Number of pages15
JournalInternational Journal of Cardiology
Volume197
DOIs
Publication statusPublished - Aug 5 2015

    Fingerprint

Keywords

  • Cardiac repair
  • Clusterin
  • EMT
  • Epicardial cells
  • Molecular rehabilitation

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

Cite this

Foglio, E., Puddighinu, G., Fasanaro, P., D'Arcangelo, D., Perrone, G. A., Mocini, D., Campanella, C., Coppola, L., Logozzi, M., Azzarito, T., Marzoli, F., Fais, S., Pieroni, L., Marzano, V., Germani, A., Capogrossi, M. C., Russo, M. A., & Limana, F. (2015). Exosomal clusterin, identified in the pericardial fluid, improves myocardial performance following MI through epicardial activation, enhanced arteriogenesis and reduced apoptosis. International Journal of Cardiology, 197, 333-347. [20664]. https://doi.org/10.1016/j.ijcard.2015.06.008