Metabolic enzyme pyruvate kinase M2 regulates platelet function and arterial thrombosis

Article: Metabolic enzyme pyruvate kinase M2 regulates platelet function and arterial thrombosis

Authors: Manasa K Nayak, Madankumar Ghatge, Gagan D Flora, Nirav Dhanesha, Manish Jain, Kathleen R Markan, Matthew J Potthoff, Steven R Lentz, Anil K Chauhan

Journal: Blood. 2020 Oct 7;blood.2020007140. doi: 10.1182/blood.2020007140. Online ahead of print.

Abstract:
Very little is known about the role of metabolic regulatory mechanisms in platelet activation and thrombosis. Dimeric pyruvate kinase M2 (PKM2) is a crucial regulator of aerobic glycolysis that facilitates the production of lactate and metabolic reprogramming. Herein, we report that limiting PKM2 dimer formation, using a small molecule inhibitor ML265, negatively regulates lactate production and glucose uptake in human and murine stimulated platelets. Furthermore, limiting PKM2 dimer formation reduced agonist-induced platelet activation, aggregation, clot retraction, and thrombus formation under arterial shear stress in vitro in both human and murine platelets. Mechanistically, limiting PKM2 dimerization downregulated PI3 kinase-mediated Akt /GSK3 signaling in human and murine platelets. To provide further evidence for the role of PKM2 in platelet function, we generated a megakaryocyte or platelet-specific PKM2-/- mutant strain (PKM2fl/flPF4Cre+). Platelet-specific PKM2 deficient mice exhibited impaired agonist-induced platelet activation, aggregation, clot retraction, PI3 kinase-mediated Akt /GSK3 signaling, and were less susceptible to arterial thrombosis in FeCl3-induced carotid and laser-injury induced mesenteric artery thrombosis models, without altering hemostasis. Wild-type mice treated with ML265 were less susceptible to arterial thrombosis with unaltered tail bleeding times. These findings reveal a major role for PKM2 in coordinating multiple aspects of platelet function, from metabolism to cellular signaling to thrombosis, and implicate PKM2 as a potential target for antithrombotic therapeutic intervention.

Link to journal online: https://ashpublications.org/blood/article-lookup/doi/10.1182/blood.2020007140