Targeting Na+/K+ ATPase alpha 1 proteins could help identify novel therapies for blood clots, thrombosis

Targeting Na+/K+ ATPase alpha 1 (ATP1A1) subunit proteins could help identify novel therapies for addressing blood clots and thrombosis, according to a new study by Marshall University researchers.

Using the Atp1a1 haplodeficient mice in a murine thrombosis model, a research team at the Marshall University Joan C. Edwards School of Medicine discovered that ATP1A1 haplodeficiency dramatically inhibited in vivo thrombosis in male mice. ATP1A1 haplodeficiency did not affect initial platelet adhesion/aggregation on injured vessel walls or collagen-coated surfaces. However, it significantly delayed additional 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 a fall in the Na+/K+ ATPase pump function. ATP1A1 heterozygosity also reduced ADP-induced AKT activation in platelets, suggesting that ATP1A1 may participate in ADP-receptor mediated platelet activation."

Oliver Li, a second-year medical student at the Joan C. Edwards School of Medicine and lead author on the study

Based in the lab of Wei Li, M.D., Ph.D., Oliver Li and his co-authors presented the research last month at the International Society on Thrombosis and Haemostasis (ISTH) during its 2022 Congress, the leading international meeting in the field of thrombosis and hemostasis, held in London, England. Oliver Li was awarded the 2022 ISTH Congress Travel Award, which rewards abstracts of outstanding quality, for his presentation.

Further study demonstrated that ATP1A1 forms a complex with P2Y12, a major ADP receptor on the platelet surface. Moreover, pretreatment of human platelets with Ouabain, an inhibitor of Na+/K+ ATPase, inhibited ADP-stimulated platelet aggregation in a dose-dependent manner. Intraperitoneal injection of Ouabain also significantly inhibited thrombosis in mice.

Rodrigo Aguilar, M.D., Renat Roytenberg, Hong Yue, M.D., Ph.D., Ellen Thompson, M.D., Sandrine Pierre, Ph.D., and Jiang Liu, M.D., Ph.D., also served as co-authors on the abstract. This work is supported by the Marshall University Institute Start Fund, the National Institutes of Health (R15HL145573 and R15HL145666), and the West Virginia IDeA Network of Biomedical Research Excellence (WV-INBRE) (P20GM103434).

Vascular thrombosis is the primary event in life threatening diseases such as myocardial infarction and stroke. Many current anti-platelet medications indicate they may cause severe side effects, e.g., excessive bleeding. Additional studies are ongoing to develop a novel regimen involving Na+/K+ ATPase-inhibition as a target for safe anti-thrombotic therapy.

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