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

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 ?-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 ?-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.