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Myocardial hypoxic stress mediates functional cardiac extracellular vesicle release

2021; Oxford University Press; Volume: 42; Issue: 28 Linguagem: Inglês

10.1093/eurheartj/ehab247

1522-9645

Achille Anselmo, Derk Frank, Laura Papa, Chiara Viviani Anselmi, Elisa Di Pasquale, Marta Mazzola, Cristina Panico, Francesca Clemente, Cristiana Soldani, Christina Pagiatakis, Rabea Hinkel, Ruth Thalmann, Reiner Kozlik-Feldmann, Michele Miragoli, Pierluigi Carullo, Marco Vacchiano, Antonio Chaves-Sanjuán, Nadia Santo, Maria Angela Losi, Matteo Carlo Ferrari, Annibale Alessandro Puca, Vincent Christiansen, Hatim Seoudy, Sandra Freitag‐Wolf, Norbert Frey, Astrid Dempfle, Mark Mercola, Giovanni Esposito, Carlo Briguori, Christian Kupatt, Gianluigi Condorelli,

MicroRNA in disease regulation

Increased shedding of extracellular vesicles (EVs)-small, lipid bilayer-delimited particles with a role in paracrine signalling-has been associated with human pathologies, e.g. atherosclerosis, but whether this is true for cardiac diseases is unknown.Here, we used the surface antigen CD172a as a specific marker of cardiomyocyte (CM)-derived EVs; the CM origin of CD172a+ EVs was supported by their content of cardiac-specific proteins and heart-enriched microRNAs. We found that patients with aortic stenosis, ischaemic heart disease, or cardiomyopathy had higher circulating CD172a+ cardiac EV counts than did healthy subjects. Cellular stress was a major determinant of EV release from CMs, with hypoxia increasing shedding in in vitro and in vivo experiments. At the functional level, EVs isolated from the supernatant of CMs derived from human-induced pluripotent stem cells and cultured in a hypoxic atmosphere elicited a positive inotropic response in unstressed CMs, an effect we found to be dependent on an increase in the number of EVs expressing ceramide on their surface. Of potential clinical relevance, aortic stenosis patients with the highest counts of circulating cardiac CD172a+ EVs had a more favourable prognosis for transcatheter aortic valve replacement than those with lower counts.We identified circulating CD172a+ EVs as cardiac derived, showing their release and function and providing evidence for their prognostic potential in aortic stenosis patients.