Scientific publications

Selective increase of cardiomyocyte derived extracellular vesicles after experimental myocardial infarction and functional effects on the endothelium

Rodriguez JA (1), Orbe J (1), Saenz-Pipaon G (2), Abizanda G (3), Gebara N (2), Radulescu F (2), Azcarate PM (4), Alonso-Perez L (4), Merino D (5), Prosper F (6), Paramo JA (7), Roncal C (8).

(1) Laboratory of Atherothrombosis, Program of Cardiovascular Diseases, Center for Applied Medical Research (CIMA)-University of Navarra, Spain; CIBERCV, Madrid, Spain; IdiSNA, Instituto de Investigación Sanitaria de Navarra, Spain.
(2) Laboratory of Atherothrombosis, Program of Cardiovascular Diseases, Center for Applied Medical Research (CIMA)-University of Navarra, Spain.
(3) IdiSNA, Instituto de Investigación Sanitaria de Navarra, Spain; Hematology Service, Clínica Universidad de Navarra, University of Navarra, Pamplona, Spain.
(4) Departamento de Cardiología, Hospital San Pedro, Logroño, Spain.
(5) Flow Cytometry and Cell Sorting Core, Health Research Institute-IDIVAL, Santander, Spain.
(6) IdiSNA, Instituto de Investigación Sanitaria de Navarra, Spain; Hematology Service, Clínica Universidad de Navarra, University of Navarra, Pamplona, Spain; CIBERONC, Madrid, Spain.
(7) Laboratory of Atherothrombosis, Program of Cardiovascular Diseases, Center for Applied Medical Research (CIMA)-University of Navarra, Spain; CIBERCV, Madrid, Spain; IdiSNA, Instituto de Investigación Sanitaria de Navarra, Spain; Hematology Service, Clínica Universidad de Navarra, University of Navarra, Pamplona, Spain.
(8) Laboratory of Atherothrombosis, Program of Cardiovascular Diseases, Center for Applied Medical Research (CIMA)-University of Navarra, Spain; CIBERCV, Madrid, Spain; IdiSNA, Instituto de Investigación Sanitaria de Navarra, Spain

Magazine: Thrombosis Research

Date: Aug 1, 2018

Hematología y Hemoterapia [SP] Cell Therapy Area [SP]

INTRODUCTION:
Wound healing after myocardial infarction (MI) is mediated by different cell types, secreted proteins, components of the extracellular matrix (ECM) and, as increasing evidences suggest, extracellular vesicles (EVs).

We aim to determine the dynamics of release and origin of EVs after MI, as well as their biological activity on endothelial cells (ECs).

METHODS:

MI was induced in WT mice and blood and tissues collected at baseline, 3, 15 and 30 days post-ligation for cardiac function (echocardiography) and histological evaluation. Circulating EVs subpopulations were measured by flow cytometry in mouse, and in a small cohort of patients with ST-segment elevation MI (STEMI, n = 6). In vitro, EVs were isolated from a cardiomyocyte cell line (HL1) and their function assayed on ECs.

RESULTS:
Leukocyte and endothelial EVs increased concomitant to inflammatory and angiogenic processes triggered by ischemia. More strikingly, cardiomyocyte EVs (connexin43+) were detected in STEMI patients and in murine MI, where a significant increase in their levels was reported at day 15 post-ischemia (p < 0.05 vs baseline).

In vitro, HL1EVs induced ECs migration (p = 0.05) and proliferation (p < 0.05), but impaired tube formation. These apparent contradictory results could be partially explained by the upregulation of MMP3, and the apoptosis and senescence genes, p53 and p16, induced by HL1EVs on ECs (p < 0.05).

CONCLUSIONS:
MI induces the release of different EVs subpopulations, including those of cardiac origin, in a preclinical model of MI and STEMI patients. In vitro, cardiomyocyte derived EVs are able to modulate endothelial function, suggesting their active role in heart repair after ischemia.

CITATION  Thromb Res. 2018 Aug 1;170:1-9. doi: 10.1016/j.thromres.2018.07.030

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