Abstract
Abstract 13626: The Glycolytic Enzyme Pyruvate Kinase M2 Regulates Deep Vein Thrombosis
Circulation (New York, N.Y.), Vol.146(S_1), p.A13626
11/08/2022
DOI: 10.1161/circ.146.suppl_1.13626
Abstract
Byline: Manasa K Nayak; Gagan Flora, Internal Medicine, Univ of Iowa, Iowa City, IA; Prakash Doddapattar, Internal Medicine, Univ of Iowa, Iowa City, IA; Anil K Chauhan, Internal Medicine, Univ of Iowa, Iowa City, IA Introduction: Current treatment regimen for deep vein thrombosis (DVT) includes anticoagulants or surgical intervention. While effective, anticoagulants exhibit a bleeding risk that limits their use. Activated platelets release pro-thrombotic chemokines such as platelet factor 4 (PF4) from their ð-granules and are known to potentiate DVT via promoting neutrophil extracellular traps (NETs). Recently, we have shown that dimeric pyruvate kinase M2 (PKM2) regulates platelet function and arterial thrombosis without affecting hemostasis. However, the role of platelet-specific PKM2 in modulating NETosis and DVT remains unexplored. Methods: Susceptibility to DVT was evaluated in the flow-restricted inferior vena cava (IVC) stenosis model in PKM2fl/flPF4Cre+/- mice. The littermate PKM2fl/flPF4Cre-/- (abbreviated as PKM2fl/fl) was used as control. Next, we evaluated whether wild-type mice infused with a specific inhibitor of dimeric-PKM2, ML265, reduced DVT susceptibility in the IVC stenosis model. Results: The platelet-specific PKM2-/- mice were less susceptible to DVT in the IVC stenosis model. The PF4 secretion from ð-granules was significantly inhibited in agonist-stimulated platelets from PKM2fl/flPF4Cre+ mice compared to the platelets from PKM2fl/fl mice. SNAP-23 phosphorylation regulates SNARE protein complex-mediated mediated secretion from ð granules. Therefore, we determined the mechanistic role of PKM2 in modulating SNAP-23-mediated PF4 secretion in platelets. In agonist-stimulated PKM2-/- platelets, SNAP23 phosphorylation and PF4 secretion were reduced compared to agonist-stimulated WT platelets. In addition, neutrophils treated with stimulated platelet releasates from PKM2fl/flPF4Cre+ mice exhibited significantly reduced NET formation in contrast to PKM2fl/fl mice. Finally, we demonstrate that ML265-treated mice showed reduced susceptibility to DVT in the IVC stenosis model. Conclusions: Our results suggest an essential role of PKM2 in regulating SNAP-23 mediated ð-granule release, NETosis, and subsequent development of DVT.
Details
- Title: Subtitle
- Abstract 13626: The Glycolytic Enzyme Pyruvate Kinase M2 Regulates Deep Vein Thrombosis
- Creators
- Manasa K NayakGagan FloraPrakash DoddapattarAnil K Chauhan
- Resource Type
- Abstract
- Publication Details
- Circulation (New York, N.Y.), Vol.146(S_1), p.A13626
- Publisher
- Lippincott Williams & Wilkins, WK Health
- DOI
- 10.1161/circ.146.suppl_1.13626
- ISSN
- 0009-7322
- eISSN
- 1524-4539
- Language
- English
- Date published
- 11/08/2022
- Description audience
- Professional
- Academic Unit
- Internal Medicine; Hematology, Oncology, and Blood & Marrow Transplantation
- Record Identifier
- 9984361717802771
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