Salvianolic acid B inhibits thrombosis and directly blocks the thrombin catalytic site.

Autor:	Neves MAD; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada.; Keenan Research Centre for Biomedical Science, St. Michael's Hospital, Toronto, Ontario, Canada.; Toronto Platelet Immunobiology Group, University of Toronto, Toronto, Ontario, Canada.; Canadian Blood Services Centre for Innovation, Toronto, Ontario, Canada., Ni TT; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada.; Keenan Research Centre for Biomedical Science, St. Michael's Hospital, Toronto, Ontario, Canada.; Toronto Platelet Immunobiology Group, University of Toronto, Toronto, Ontario, Canada., Mackeigan DT; Keenan Research Centre for Biomedical Science, St. Michael's Hospital, Toronto, Ontario, Canada.; Toronto Platelet Immunobiology Group, University of Toronto, Toronto, Ontario, Canada.; Department of Physiology, University of Toronto, Toronto, Ontario, Canada., Shoara AA; Keenan Research Centre for Biomedical Science, St. Michael's Hospital, Toronto, Ontario, Canada.; Toronto Platelet Immunobiology Group, University of Toronto, Toronto, Ontario, Canada.; Canadian Blood Services Centre for Innovation, Toronto, Ontario, Canada.; Department of Physiology, University of Toronto, Toronto, Ontario, Canada.; Department of Chemistry and Centre for Research on Biomolecular Interactions, York University, Toronto, Ontario, Canada., Lei X; Keenan Research Centre for Biomedical Science, St. Michael's Hospital, Toronto, Ontario, Canada.; Toronto Platelet Immunobiology Group, University of Toronto, Toronto, Ontario, Canada., Slavkovic S; Keenan Research Centre for Biomedical Science, St. Michael's Hospital, Toronto, Ontario, Canada.; Toronto Platelet Immunobiology Group, University of Toronto, Toronto, Ontario, Canada.; Canadian Blood Services Centre for Innovation, Toronto, Ontario, Canada., Yu SY; Keenan Research Centre for Biomedical Science, St. Michael's Hospital, Toronto, Ontario, Canada.; Toronto Platelet Immunobiology Group, University of Toronto, Toronto, Ontario, Canada., Stratton TW; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada.; Keenan Research Centre for Biomedical Science, St. Michael's Hospital, Toronto, Ontario, Canada.; Toronto Platelet Immunobiology Group, University of Toronto, Toronto, Ontario, Canada., Gallant RC; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada.; Keenan Research Centre for Biomedical Science, St. Michael's Hospital, Toronto, Ontario, Canada.; Toronto Platelet Immunobiology Group, University of Toronto, Toronto, Ontario, Canada., Zhang D; Keenan Research Centre for Biomedical Science, St. Michael's Hospital, Toronto, Ontario, Canada.; Toronto Platelet Immunobiology Group, University of Toronto, Toronto, Ontario, Canada., Xu XR; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada.; Keenan Research Centre for Biomedical Science, St. Michael's Hospital, Toronto, Ontario, Canada.; Toronto Platelet Immunobiology Group, University of Toronto, Toronto, Ontario, Canada.; Canadian Blood Services Centre for Innovation, Toronto, Ontario, Canada., Fernandes C; Keenan Research Centre for Biomedical Science, St. Michael's Hospital, Toronto, Ontario, Canada.; Toronto Platelet Immunobiology Group, University of Toronto, Toronto, Ontario, Canada., Zhu G; Keenan Research Centre for Biomedical Science, St. Michael's Hospital, Toronto, Ontario, Canada.; Toronto Platelet Immunobiology Group, University of Toronto, Toronto, Ontario, Canada.; Canadian Blood Services Centre for Innovation, Toronto, Ontario, Canada., Hu X; Keenan Research Centre for Biomedical Science, St. Michael's Hospital, Toronto, Ontario, Canada.; Toronto Platelet Immunobiology Group, University of Toronto, Toronto, Ontario, Canada., Chazot N; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada.; Keenan Research Centre for Biomedical Science, St. Michael's Hospital, Toronto, Ontario, Canada.; Toronto Platelet Immunobiology Group, University of Toronto, Toronto, Ontario, Canada., Donaldson LW; Department of Chemistry and Centre for Research on Biomolecular Interactions, York University, Toronto, Ontario, Canada., Johnson PE; Department of Chemistry and Centre for Research on Biomolecular Interactions, York University, Toronto, Ontario, Canada., Connelly K; Keenan Research Centre for Biomedical Science, St. Michael's Hospital, Toronto, Ontario, Canada.; Department of Physiology, University of Toronto, Toronto, Ontario, Canada.; Division of Cardiology, St. Michael's Hospital, Toronto, Ontario, Canada.; Department of Medicine, University of Toronto, Toronto, Ontario, Canada., Rand M; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada.; Toronto Platelet Immunobiology Group, University of Toronto, Toronto, Ontario, Canada.; Division of Hematology, The Hospital for Sick Children, Toronto, Ontario, Canada.; Department of Biochemistry, University of Toronto, Toronto, Ontario, Canada., Wang Y; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada.; Keenan Research Centre for Biomedical Science, St. Michael's Hospital, Toronto, Ontario, Canada.; Toronto Platelet Immunobiology Group, University of Toronto, Toronto, Ontario, Canada.; Canadian Blood Services Centre for Innovation, Toronto, Ontario, Canada.; Division of Clinical and Metabolic Genetics, The Hospital for Sick Children, Toronto, Ontario, Canada.; Genetics and Genome Biology Program, Peter Gilgan Centre for Research and Learning, Toronto, Ontario, Canada.; Department of Paediatrics, University of Toronto, Toronto, Ontario, Canada., Ni H; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada.; Keenan Research Centre for Biomedical Science, St. Michael's Hospital, Toronto, Ontario, Canada.; Toronto Platelet Immunobiology Group, University of Toronto, Toronto, Ontario, Canada.; Canadian Blood Services Centre for Innovation, Toronto, Ontario, Canada.; Department of Physiology, University of Toronto, Toronto, Ontario, Canada.; Department of Medicine, University of Toronto, Toronto, Ontario, Canada.
Jazyk:	angličtina
Zdroj:	Research and practice in thrombosis and haemostasis [Res Pract Thromb Haemost] 2024 May 17; Vol. 8 (4), pp. 102443. Date of Electronic Publication: 2024 May 17 (Print Publication: 2024).
DOI:	10.1016/j.rpth.2024.102443
Abstrakt:	Background: Salvianolic acid B (SAB) is a major component of Salvia miltiorrhiza root (Danshen), widely used in East/Southeast Asia for centuries to treat cardiovascular diseases. Danshen depside salt, 85% of which is made up of SAB, is approved in China to treat chronic angina. Although clinical observations suggest that Danshen extracts inhibited arterial and venous thrombosis, the exact mechanism has not been adequately elucidated. Objective: To delineate the antithrombotic mechanisms of SAB. Methods: We applied platelet aggregation and coagulation assays, perfusion chambers, and intravital microscopy models. The inhibition kinetics and binding affinity of SAB to thrombin are measured by thrombin enzymatic assays, intrinsic fluorescence spectrophotometry, and isothermal titration calorimetry. We used molecular in silico docking models to predict the interactions of SAB with thrombin. Results: SAB dose-dependently inhibited platelet activation and aggregation induced by thrombin. SAB also reduced platelet aggregation induced by adenosine diphosphate and collagen. SAB attenuated blood coagulation by modifying fibrin network structures and significantly decreased thrombus formation in mouse cremaster arterioles and perfusion chambers. The direct SAB-thrombin interaction was confirmed by enzymatic assays, intrinsic fluorescence spectrophotometry, and isothermal titration calorimetry. Interestingly, SAB shares key structural similarities with the trisubstituted benzimidazole class of thrombin inhibitors, such as dabigatran. Molecular docking models predicted the binding of SAB to the thrombin active site. Conclusion: Our data established SAB as the first herb-derived direct thrombin catalytic site inhibitor, suppressing thrombosis through both thrombin-dependent and thrombin-independent pathways. Purified SAB may be a cost-effective agent for treating arterial and deep vein thrombosis. (© 2024 The Authors.)
Databáze:	MEDLINE
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