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miR-146a mimic therapy protects against platelet-mediated thrombosis

Fecha de publicación: Fecha Ahead of Print:

Autores de IIS La Fe

Participantes ajenos a IIS La Fe

  • Águila S.
  • Zapata-Martínez L.
  • Arroyo A.B.
  • García-Barberá N.
  • Carrillo-Tornel S.
  • Guijarro-Carrillo P.J.
  • Lozano M.L.
  • Payrastre B.
  • Rivera J.
  • Gratacap M.-P.
  • Lahoz A.
  • Kortylewski M.
  • González-Conejero R.
  • Martínez C.

Grupos

Abstract

miR-146a exhibits variable expression levels in humans due to rs2431697, which is associated with cardiovascular events. However, the functional mechanisms linking this genotype with the occurrence of thrombotic events remain unknown. Here, we found that miR-146a partial deficiency was associated with increased platelet activation and a higher incidence of cardiovascular events during hospitalization in patients with community-acquired pneumonia. Accordingly, platelets from miR-146a -/- mice were hyperreactive to agonists under static and flow conditions vs. wild type. Metabolomics indicated that miR-146a -/- platelets had elevated oxygen consumption rate and acyl-carnitine/carnitine ratio and reduced fatty acid levels. Consistently, miR-146a -/- platelets exhibited higher Cpt1a expression, a limiting enzyme of fatty acid ß-oxidation. Platelet supplementation with palmitate or etomoxir, a Cpt1a inhibitor, increased or normalized miR-146a -/- platelets’ response, respectively, demonstrating that this deficiency enhanced fatty acid ß-oxidation. In vivo , miR-146a -/- mice demonstrated accelerated lung occlusion leading to a higher mortality rate in a systemic thrombotic model. Injection of a miR-146a mimic targeting myeloid cells in miR-146a -/- mice prevented platelet aggregation in lungs by fully protecting them against thrombosis. In summary, our findings show that miR-146a deficiency leads to platelet hyperreactivity through metabolic reprogramming. Elevating miR-146a levels may be a therapy for preventing cardiovascular events. © 2026 The Authors.

Copyright © 2026 The Authors. Published by Elsevier Inc. All rights reserved.

Datos de la publicación

ISSN/ISSNe:
1525-0016, 1525-0024

MOLECULAR THERAPY  CELL PRESS

Tipo:
Article
Páginas:
5333-5351
PubMed:
42444128
Enlace a otro recurso:
www.scopus.com
Factor de Impacto:
3,064 SCImago ℠
Cuartil:
Q1 SCImago ℠

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Keywords

  • community-acquired pneumonia; fatty acid oxidation; metabolism; miRNAs; mouse model; platelets; therapy; thrombosis

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