The metabolic enzyme pyruvate kinase M2 regulates platelet function and arterial thrombosis

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

Research output: Contribution to journalArticlepeer-review

3 Scopus citations

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 the 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 phosphatidylinositol 3-kinase (PI3K)-mediated protein kinase B or serine/threonine-specific protein kinase (Akt)/glycogen synthase kinase 3 (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, and PI3K-mediated Akt/GSK3 signaling and were less susceptible to arterial thrombosis in FeCl3 injury–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. Key Points: • Platelet activation increases PKM2 dimer formation, which modulates platelet functions and arterial thrombosis. • PKM2 regulates PI3K-mediated Akt and GSK3 signaling.

Original languageEnglish
Pages (from-to)1658-1668
Number of pages11
JournalBlood
Volume137
Issue number12
DOIs
StatePublished - Mar 25 2021

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