Abstract Number: OC 77.2
Meeting: ISTH 2022 Congress
Background: Thrombosis is a major cause of myocardial infarction and ischemic stroke. Sodium/potassium ATPase (NKA) is composited by alpha and beta subunits and plays an important role in maintaining the sodium and potassium gradient across the cell membrane. NKA has signaling functions, and its α1 subunit (ATP1A1) binds to and inhibits the activity of Src, a tyrosine kinase, which plays a critical role during platelet activation.
Aims: To test the hypothesis that ATP1A1 participates in platelet signaling activation and is an anti-platelet and anti-thrombotic target.
Methods: Wildtype and ATP1A1 heterozygous mice aged 10-14 weeks were used. A FeCl3-induced carotid artery injury thrombosis model in combination with intravital microscopy was used for in vivo thrombosis study. Platelet aggregation and Cellix flow chamber assays were used to evaluate in vitro platelet function. Western blot, co-IP, and blue native PAGE assays were used for the characterization of protein expressions and protein complex formations.
Results: ATP1A1 heterozygosity dramatically reduced its expression on platelets and inhibited in vivo thrombosis in male but not female mice. ATP1A1 heterozygosity did not affect initial platelet adhesion/aggregation on injured vessel walls and collagen-coated surfaces. However, it significantly delayed second wave platelet activation in vivo and inhibited ADP-induced platelet aggregation in vitro. ATP1A1 heterozygosity did not affect platelet intracellular sodium concentration, suggesting that the observed anti-thrombotic phenotype is not due to the altered NKA function. Intraperitoneal injection of the NKA inhibitor Ouabain (100 ng/g of body weight) for 24 hours significantly inhibited thrombosis in mice. ATP1A1 heterozygosity showed reduced ADP-induced AKT activation in platelets. ATP1A1 forms a complex with the ADP receptor P2Y12, and pretreatment of human platelets with Ouabain inhibited ADP-stimulated platelet aggregation in a dose-dependent manner.
Conclusion(s): ATP1A1 participates in platelet ADP signaling, which is essential for ADP-induced platelet activation. Targeting ATP1A1 could be a novel strategy for antiplatelet and antithrombotic therapy.
To cite this abstract in AMA style:Li O, Aguilar R, Roytenberg R, Yue H, Thompson E, Pierre S, Liu J, Li W. Na+/K+ ATPase alpha 1 subunit participates in platelet signaling and is a potential anti-thrombotic target [abstract]. https://abstracts.isth.org/abstract/na-k-atpase-alpha-1-subunit-participates-in-platelet-signaling-and-is-a-potential-anti-thrombotic-target/. Accessed September 24, 2023.
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