دورية أكاديمية
أعرض في EDS

Role of SHP2 (PTPN11) in glycoprotein VI-dependent thrombus formation: Improved platelet responsiveness by the allosteric drug SHP099 in Noonan syndrome patients.

التفاصيل البيبلوغرافية
العنوان: Role of SHP2 (PTPN11) in glycoprotein VI-dependent thrombus formation: Improved platelet responsiveness by the allosteric drug SHP099 in Noonan syndrome patients.
المؤلفون: Fernández DI; Platelet Proteomics Group, Center for Research in Molecular Medicine and Chronic Diseases (CiMUS), Universidade de Santiago de Compostela, and Instituto de Investigación Sanitaria de Santiago (IDIS), 15706 Santiago de Compostela, Spain; Department of Biochemistry, CARIM, Maastricht University, 6200 MD Maastricht, the Netherlands. Electronic address: d.fernandezdelafuent@maastrichtuniversity.nl., Diender M; Department of Pediatric Hematology, Amalia children's hospital, Radboud UMC, Nijmegen, the Netherlands., Hermida-Nogueira L; Platelet Proteomics Group, Center for Research in Molecular Medicine and Chronic Diseases (CiMUS), Universidade de Santiago de Compostela, and Instituto de Investigación Sanitaria de Santiago (IDIS), 15706 Santiago de Compostela, Spain., Huang J; Platelet Proteomics Group, Center for Research in Molecular Medicine and Chronic Diseases (CiMUS), Universidade de Santiago de Compostela, and Instituto de Investigación Sanitaria de Santiago (IDIS), 15706 Santiago de Compostela, Spain; Department of Biochemistry, CARIM, Maastricht University, 6200 MD Maastricht, the Netherlands; ISAS Leibniz-Institut fur Analytische Wissenschaften-ISAS-e.V., 44227 Dortmund, Germany., Veiras S; Department of Anesthesiology and Intensive Care Medicine, Clinical University Hospital of Santiago, Santiago de Compostela, Spain., Henskens YMC; Central Diagnostic Laboratory, Unit for Hemostasis and Transfusion, Maastricht University Medical Centre(+), Maastricht, the Netherlands., Te Loo MWM; Department of Pediatric Hematology, Amalia children's hospital, Radboud UMC, Nijmegen, the Netherlands., Heemskerk JWM; Department of Biochemistry, CARIM, Maastricht University, 6200 MD Maastricht, the Netherlands; Synapse Research Institute, Kon. Emmaplein 7, 6217 KD, Maastricht, the Netherlands., Kuijpers MJE; Department of Biochemistry, CARIM, Maastricht University, 6200 MD Maastricht, the Netherlands; Thrombosis Expertise Centre, Heart and Vascular Centre, Maastricht University Medical Centre(+), Maastricht, the Netherlands. Electronic address: Marijke.Kuijpers@maastrichtuniversity.nl., García Á; Platelet Proteomics Group, Center for Research in Molecular Medicine and Chronic Diseases (CiMUS), Universidade de Santiago de Compostela, and Instituto de Investigación Sanitaria de Santiago (IDIS), 15706 Santiago de Compostela, Spain.
المصدر: Thrombosis research [Thromb Res] 2023 Aug; Vol. 228, pp. 105-116. Date of Electronic Publication: 2023 Jun 05.
نوع المنشور: Journal Article
اللغة: English
بيانات الدورية: Publisher: Pergamon Press Country of Publication: United States NLM ID: 0326377 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1879-2472 (Electronic) Linking ISSN: 00493848 NLM ISO Abbreviation: Thromb Res Subsets: MEDLINE
أسماء مطبوعة: Original Publication: Elmsford, N. Y., Pergamon Press.
مواضيع طبية MeSH: Noonan Syndrome*/drug therapy , Noonan Syndrome*/genetics , Noonan Syndrome*/metabolism , Thrombosis*, Humans ; Blood Platelets/metabolism ; Thromboplastin/metabolism ; Platelet Glycoprotein GPIIb-IIIa Complex/metabolism ; Collagen/metabolism ; Fibrin/metabolism ; Platelet Membrane Glycoproteins ; Protein Tyrosine Phosphatase, Non-Receptor Type 11/metabolism
مستخلص: Introduction: The protein tyrosine phosphatase SHP2 (PTPN11) is a negative regulator of glycoprotein VI (GPVI)-induced platelet signal under certain conditions. Clinical trials with derivatives of the allosteric drug SHP099, inhibiting SHP2, are ongoing as potential therapy for solid cancers. Gain-of-function mutations of the PTPN11 gene are observed in part of the patients with the Noonan syndrome, associated with a mild bleeding disorder. Assessment of the effects of SHP2 inhibition in platelets from controls and Noonan syndrome patients.
Materials and Methods: Washed human platelets were incubated with SHP099 and stimulated with collagen-related peptide (CRP) for stirred aggregation and flow cytometric measurements. Whole-blood microfluidics assays using a dosed collagen and tissue factor coating were performed to assess shear-dependent thrombus and fibrin formation. Effects on clot formation were evaluated by thromboelastometry.
Results: Pharmacological inhibition of SHP2 did not alter GPVI-dependent platelet aggregation under stirring, but it enhanced integrin αIIbβ3 activation in response to CRP. Using whole-blood microfluidics, SHP099 increased the thrombus buildup on collagen surfaces. In the presence of tissue factor and coagulation, SHP099 increased thrombus size and reduced time to fibrin formation. Blood from PTPN11-mutated Noonan syndrome patients, with low platelet responsiveness, after ex vivo treatment with SHP099 showed a normalized platelet function. In thromboelastometry, SHP2 inhibition tended to increase tissue factor-induced blood clotting profiles with tranexamic acid, preventing fibrinolysis.
Conclusion: Pharmacological inhibition of SHP2 by the allosteric drug SHP099 enhances GPVI-induced platelet activation under shear conditions with a potential to improve platelet functions of Noonan syndrome patients.
Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)
فهرسة مساهمة: Keywords: Glycoprotein VI; Noonan syndrome; PTPN11; Platelet; SHP099; SHP2
المشرفين على المادة: 0 (SHP099)
9035-58-9 (Thromboplastin)
0 (Platelet Glycoprotein GPIIb-IIIa Complex)
9007-34-5 (Collagen)
9001-31-4 (Fibrin)
0 (Platelet Membrane Glycoproteins)
EC 3.1.3.48 (PTPN11 protein, human)
EC 3.1.3.48 (Protein Tyrosine Phosphatase, Non-Receptor Type 11)
تواريخ الأحداث: Date Created: 20230611 Date Completed: 20230703 Latest Revision: 20231129
رمز التحديث: 20240628
DOI: 10.1016/j.thromres.2023.06.001
PMID: 37302266
قاعدة البيانات: MEDLINE
الوصف
تدمد:1879-2472
DOI:10.1016/j.thromres.2023.06.001