The Na/K-ATPase α1 subunit fine-tunes platelet P2Y12 function and mediates sex dimorphism–associated thrombosis
Year: 2025
Type: article
Abstract: ABSTRACT: Sex differences are well recognized in thrombotic diseases, but the underlying mechanisms remain unclear. The sodium/potassium ATPase (NKA), composed of α and β subunits, regulates ion homeostasis and plays a key role in cardiovascular function. We investigated whether the NKA α1 subunit influences platelet activation and thrombosis. Using the ferric chloride (FeCl3)-induced carotid artery injury thrombosis model in wild-type (WT; α1+/+) and NKA α1 heterozygous (α1+/-) mice, we found that NKA α1 haploinsufficiency significantly inhibited thrombosis in males but not in females, without affecting hemostasis. Platelet NKA α1 expression was halved in α1+/- mice, but sodium homeostasis remained unchanged. Transfusion of α1+/- platelets into thrombocytopenic WT mice prolonged the time to occlusive thrombus formation. Low-dose ouabain or marinobufagenin, which bind NKA α1, suppressed thrombosis. Mechanistically, α1 interacted with P2Y12, and this interaction was disrupted by a leucine-glycine-leucine (LGL)→serine-phenylalanine-threonine mutation in either partner or by the LGL peptide. NKA α1 haploinsufficiency, ouabain, and LGL peptide treatment all reduced ADP-induced platelet aggregation. Female mice exhibited higher platelet α1 expression and shorter thrombosis times than males. Gonadectomy had no effect in females but abolished the antithrombotic phenotype in α1+/- males, whereas orchiectomy increased platelet α1 expression. Although α1 haploinsufficiency did not affect thrombosis in the 10% FeCl3 model, it prolonged thrombosis time in mice treated with low-dose clopidogrel or prasugrel, which alone had no effect. These findings identify NKA α1 as a key regulator of sex-specific platelet activation and thrombosis, suggesting its potential as a biomarker for thrombotic risk and a therapeutic target for antiplatelet and antithrombotic therapy.
Source: Blood Advances
Language: English
Subfield: Hematology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $3,800
Awards: G1621506528, G1739031488, Dissection of the mechanisms underlying sex-influenced cardiovascular disease, G2592540264, G3325417774, G360897169, The Role of Oxidative Signaling through Na/K-ATPase in PNx-induced Anemia, ATP1A1-dependent Regulation of Sodium Handling by the Renal Proximal Tubule: Mechanism and Implications in Salt-Sensitivity, G5514976981, G5871254648, Thymidine Phosphorylase: a Novel Target of Antiplatelet Therapy, G7251701605, The Na/K-ATPase receptor function as a novel therapeutic target in myocardial infarction, West Virginia Clinical and Translational Science Institute: Improving Health through Partnerships and Transformative Research, G9000105446, G9000133327, G9000224999, G9000257662, West Virginia IDeA Network of Biomedical Research Excellence (WV-INBRE), Sodium Pump, Sex Hormones, and Thrombosis
OpenAlex ID: W4415396019