Antithrombotic effects of targeting alpha IIb beta 3 signaling in platelets

作者：Ablooglu Ararat J^*; Kang Jian; Petrich Brian G; Gin**erg Mark H; Shattil Sanford J

来源：Blood, 2009, 113(15): 3585-3592.

DOI：10.1182/blood-2008-09-180687

alpha IIb beta 3 interaction with fibrinogen promotes Src-dependent platelet spreading in vitro. To determine the consequences of this outside-in signaling pathway in vivo, a "beta 3(Delta 760-762)" knockin mouse was generated that lacked the 3 C-terminal beta 3 residues (arginine-glycine-threonine [RGT]) necessary for alpha IIb beta 3 interaction with c-Src, but retained beta 3 residues necessary for talin-dependent fibrinogen binding. beta 3(Delta 760-762) mice were compared with wild-type beta 3(+/+) littermates, beta 3(+/-) heterozygotes, and knockin mice where beta 3 RGT was replaced by beta 1 C-terminal cysteine-glycine-lysine (EGK) to potentially enable signaling by Src kinases other than c-Src. Whereas beta 3(+/+), beta 3(+/-) and beta 3/beta 1(EGK) platelets spread and underwent tyrosine phosphorylation normally on fibrinogen, beta 3(Delta 760-762) platelets spread poorly and exhibited reduced tyrosine phosphorylation of c-Src substrates, including beta 3 (Tyr(747)). Unlike control mice, beta 3(Delta 760-762) mice were protected from carotid artery thrombosis after vessel injury with FeCl3. Some beta 3(Delta 760-762) mice exhibited prolonged tail bleeding times; however, none demonstrated spontaneous bleeding, excess bleeding after surgery, fecal blood loss, or anemia. Fibrinogen binding to beta 3(Delta 760-762) 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 beta 3 RGT disrupts c-Src-mediated alpha IIb beta 3 signaling and confers protection from arterial thrombosis. Consequently, targeting alpha IIb beta 3 signaling may represent a feasible antithrombotic strategy. (Blood. 2009; 113: 3585-3592)

• 出版日期2009-4-9