Antithrombotic effects of targeting αIIbβ3 signaling in platelets
αIIbβ3 interaction with fibrinogen promotes Src-dependent platelet spreading in vitro. To determine the consequences of this outside-in signaling pathway in vivo, a “β3(Δ760-762)” knockin mouse was generated that lacked the 3 C-terminal β3 residues (arginine-glycine-threonine [RGT]) necessary for αI...
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Veröffentlicht in: | Blood 2009-04, Vol.113 (15), p.3585-3592 |
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Sprache: | eng |
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Zusammenfassung: | αIIbβ3 interaction with fibrinogen promotes Src-dependent platelet spreading in vitro. To determine the consequences of this outside-in signaling pathway in vivo, a “β3(Δ760-762)” knockin mouse was generated that lacked the 3 C-terminal β3 residues (arginine-glycine-threonine [RGT]) necessary for αIIbβ3 interaction with c-Src, but retained β3 residues necessary for talin-dependent fibrinogen binding. β3(Δ760-762) mice were compared with wild-type β3+/+ littermates, β3+/− heterozygotes, and knockin mice where β3 RGT was replaced by β1 C-terminal cysteine-glycine-lysine (EGK) to potentially enable signaling by Src kinases other than c-Src. Whereas β3+/+, β3+/− and β3/β1(EGK) platelets spread and underwent tyrosine phosphorylation normally on fibrinogen, β3(Δ760-762) platelets spread poorly and exhibited reduced tyrosine phosphorylation of c-Src substrates, including β3 (Tyr747). Unlike control mice, β3(Δ760-762) mice were protected from carotid artery thrombosis after vessel injury with FeCl3. Some β3(Δ760-762) mice exhibited prolonged tail bleeding times; however, none demonstrated spontaneous bleeding, excess bleeding after surgery, fecal blood loss, or anemia. Fibrinogen binding to β3(Δ760-762) platelets was normal in response to saturating concentrations of protease-activated receptor 4 or glycoprotein VI agonists, but responses to adenosine diphosphate were impaired. Thus, deletion of β3 RGT disrupts c-Src–mediated αIIbβ3 signaling and confers protection from arterial thrombosis. Consequently, targeting αIIbβ3 signaling may represent a feasible antithrombotic strategy. |
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ISSN: | 0006-4971 1528-0020 |
DOI: | 10.1182/blood-2008-09-180687 |