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

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

By using the Atp1a1 Haplodeficient mice in a model of murine thrombosis, a research team from Marshall University Joan C. Edwards School of Medicine found that haplodeficiency in ATP1A1 significantly inhibited thrombosis in vivo in male mice. ATP1A1 haplodeficiency did not affect initial platelet adhesion/aggregation to injured vessel walls or collagen-coated surfaces. However, it significantly delayed further 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 drop in 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, second-year medical student at the Joan C. Edwards School of Medicine and lead author of the study

Based in the lab of Wei Li, MD, Ph.D., Oliver Li and his co-authors presented the research last month to the International Society of Thrombosis and Hemostasis (ISTH) at its 2022 congress, the main international meeting in the field of thrombosis and hemostasis, held in London, England. Oliver Li received the 2022 ISTH Congress Travel Award, which recognizes abstracts of exceptional quality, for his presentation.

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

Rodrigo Aguilar, MD, Renat Roytenberg, Hong Yue, MD, Ph.D., Ellen Thompson, MD, Sandrine Pierre, Ph.D., and Jiang Liu, MD, Ph.D., were also co-authors of 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 main event in life-threatening diseases such as myocardial infarction and stroke. Many current antiplatelet drugs state that they can cause serious side effects, such as excessive bleeding. Further studies are underway to develop a new treatment regimen involving Na+/K+ ATPase inhibition as a target for safe anti-thrombotic therapy.

Source:

Marshall University Joan C. Edwards School of Medicine

Irene B. Bowles