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

doi:10.1182/blood.2020007140

Back

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

Journal article

Open access

Peer reviewed

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 and Anil K Chauhan

Blood, Vol.137(12), pp.1658-1668

03/25/2021

DOI: 10.1182/blood.2020007140

PMID: 33027814

Files and links (1)

url

https://doi.org/10.1182/blood.2020007140View

Published (Version of record) Open Access

Abstract

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.

Details

Title: Subtitle: The metabolic enzyme pyruvate kinase M2 regulates platelet function and arterial thrombosis
Creators: Manasa K Nayak - Department of Internal Medicine, Division of Hematology/Oncology, and
Madankumar Ghatge - Department of Internal Medicine, Division of Hematology/Oncology, and
Gagan D Flora - Department of Internal Medicine, Division of Hematology/Oncology, and
Nirav Dhanesha - Department of Internal Medicine, Division of Hematology/Oncology, and
Manish Jain - Department of Internal Medicine, Division of Hematology/Oncology, and
Kathleen R Markan - Department of Neuroscience and Pharmacology, University of Iowa, Iowa City, IA; and
Matthew J Potthoff - Department of Neuroscience and Pharmacology, University of Iowa, Iowa City, IA; and, Department of Veterans Affairs Medical Center, Iowa City, IA
Steven R Lentz - Department of Internal Medicine, Division of Hematology/Oncology, and
Anil K Chauhan - Department of Internal Medicine, Division of Hematology/Oncology, and
Resource Type: Journal article
Publication Details: Blood, Vol.137(12), pp.1658-1668
DOI: 10.1182/blood.2020007140
PMID: 33027814
NLM abbreviation: Blood
ISSN: 0006-4971
eISSN: 1528-0020
Language: English
Date published: 03/25/2021
Academic Unit: Hematology, Oncology, and Blood & Marrow Transplantation; Iowa Neuroscience Institute; Neuroscience and Pharmacology; Internal Medicine
Record Identifier: 9984070784602771

Metrics

14 Record Views

63 Times Cited - Web of Science