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Abstract
Vasodilator-stimulated phosphoprotein (VASP) is a member of actin regulatory proteins implicated in platelet adhesion. In addition, phosphorylation of VASP is utilised for the assessment of platelet reactivity in patients treated with P2Y12 receptor antagonists, a class of antiplatelet agents. However, the role of VASP in platelet aggregation, thrombogenesis, haemostasis, and the antiplatelet effect of P2Y12 receptor antagonists remains unclear. We investigated these effects using heterozygous and homozygous VASP knockout rats generated with a CRISPR/Cas9 system. Baseline characteristics, such as haematology and other biochemical parameters, were comparable among the genotypes. In vitro platelet aggregation stimulated by adenosine diphosphate (ADP) or collagen, P-selectin expression of rat platelets treated with ADP, and in vivo thrombocytopenia induced by collagen were also comparable among the genotypes. In addition, in vivo thrombogenesis in a ferric chloride-induced arterial thrombosis model and bleeding time were also comparable among the genotypes. Furthermore, the in vitro antiplatelet effect of prasugrel, a third-generation P2Y12 receptor antagonist, was unaffected by VASP knockout. Although phosphorylated VASP is still an important surrogate marker specific for P2Y12 antagonists, our findings demonstrate that VASP is not a major mediator of platelet aggregation, thrombogenesis, haemostasis, and the antiplatelet effect of prasugrel in rats.
Highlights
Coronary artery disease (CAD) is the leading cause of death and disability in developed countries[1]
Western blot analysis of various organs revealed global vasodilator-stimulated phosphoprotein (VASP) deletion in VASP−/− rats (Fig. 1), whereas β-actin expression was confirmed in VASP+/+, VASP+/−, and VASP−/− rats (Supplementary Fig. S2)
We thought that VASP knockout rats would offer further insight into VASP function in research on thrombosis and haemostasis
Summary
Coronary artery disease (CAD) is the leading cause of death and disability in developed countries[1]. Upon stimulation with ADP, cyclic AMP (cAMP) in platelets decreased via P2Y12 receptor-Gi proteins function and consistently VASP Ser[157] phosphorylation decreased[14,15]. Platelets derived from VASP knockout mice showed exaggerated fibrinogen binding when stimulated with collagen and thrombin, and this exaggerated binding was partially mediated by cyclic guanosine monophosphate (cGMP)/cAMP which activate cyclic nucleotide-dependent kinases[16,17], suggesting its involvement in physiological platelet functions. The role of VASP in in vivo platelet aggregation and thrombogenesis awaits further clarification. It is unknown whether VASP is essentially involved in the antiplatelet effect of P2Y12 receptor antagonists. We created VASP knockout rats and investigated whether VASP was directly involved in platelet activation, aggregation, thrombogenesis, and haemostasis. The role of VASP in the antiplatelet effect of prasugrel, a third-generation thienopyridine prodrug, was explored
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