Abstract Number: OC 61.1
Meeting: ISTH 2021 Congress
Background: miR-146a is a critical brake of inflammation and its reduction due to miR-SNPs has been associated with thromboinflammatory diseases. Platelets have a crucial role in thrombotic disorders and their activation includes energetically demanding processes. Accordingly, platelet metabolism has a great plasticity through oxidative phosphorylation, glycolysis and fatty acids (FA) β-oxidation. Whether miR146a levels might modify platelet function and metabolic program has not been explored.
Aims: To evaluate the influence of miR-146a deficiency in platelet metabolism and function.
Methods: Wild-type (WT) and miR-146a-/- platelet function was evaluated for activation by flow cytometry, aggregation, spreading, transmission electron microscopy and microfluidic assay. Platelet metabolism was characterized by Seahorse analyzer and untargeted metabolomic analysis. Pathophysiological impact of miR-146a deficiency was tested by tail bleeding, pulmonary thromboembolism (PTE) and arterial thrombosis in WT vs miR-146a-/- mice.
Results: miR-146a-/- platelet hyperreactivity was observed with most agonists, except ADP+U46619. Moreover, miR-146a deficient platelets had higher ROS production and phosphatydilserine exposure following thrombin activation. Oxidative phosphorylation was also higher in unstimulated deficient platelets and following the stimulation with different agonists (CRP, PAR4, Thr) increasing the maximum respiratory capacity and the spare respiratory capacity. The deep unbiased metabolic analysis showed an elevation of carnitines and a decrease of FA content indicating an enhanced FA β-oxidation. A higher TOM20 detection by western blot indicated an increase in the mitochondria content in miR-146a-/- platelets. Interestingly, miR-146a-/- platelets formed bigger and faster clots into collagen-coated channel at 1100s-1 and 4000s-1. To confirm these findings, we performed in vivo experiments. miR-146a knockout mice presented a shorter bleeding time. In addition, these mice had faster and severe occlusion of the lung in PTE and arterial thrombosis models.
Conclusions: miR-146-/- platelets are hyperreactive due to a metabolism shift to FA β-oxidation, higher mitochondria content and an increased ROS production. These factors promote a pro-thrombotic phenotype in different murine models.
To cite this abstract in AMA style:Águila S, B Arroyo A, C Cañaveras-García J, P Fernández-Pérez M, M De los Reyes-García A, García-Barberá N, Reguilón-Gallego L, Zapata-Martínez L, Ruiz-Lorente I, Vicente V, Rivera J, Lahoz A, Gratacap MP, González-Conejero R, Martínez C. Pleiotropic Role of miR-146a in Driving Metabolism Reprogramming Causes Platelet Hyperreactivity and Thrombosis [abstract]. Res Pract Thromb Haemost. 2021; 5 (Suppl 2). https://abstracts.isth.org/abstract/pleiotropic-role-of-mir-146a-in-driving-metabolism-reprogramming-causes-platelet-hyperreactivity-and-thrombosis/. Accessed September 21, 2023.
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