血小板活化
血小板
血栓
药理学
血栓形成
趋化因子
医学
化学
布鲁顿酪氨酸激酶
癌症研究
免疫学
作者
Julian Leberzammer,Stijn M. Agten,Xavier Blanchet,Rundan Duan,Hans Ippel,Remco T. A. Megens,Christian Schulz,Maria Aslani,Johan Duchene,Yvonne Döring,Natalie Jasmin Jooss,Pengyu Zhang,Richard Brandl,Konstantin Stark,Wolfgang Siess,Kerstin Jurk,Johan W. M. Heemskerk,Tilman M Hackeng,Kevin H Mayo,Christian Weber,Philipp von Hundelshausen
出处
期刊:Blood
[American Society of Hematology]
日期:2022-04-28
卷期号:139 (17): 2691-2705
标识
DOI:10.1182/blood.2020010140
摘要
The prevention and treatment of arterial thrombosis continue to be clinically challenging, and understanding the relevant molecular mechanisms in detail may facilitate the quest to identify novel targets and therapeutic approaches that improve protection from ischemic and bleeding events. The chemokine CXCL12 augments collagen-induced platelet aggregation by activating its receptor CXCR4. Here we show that inhibition of CXCR4 attenuates platelet aggregation induced by collagen or human plaque homogenate under static and arterial flow conditions by antagonizing the action of platelet-secreted CXCL12. We further show that platelet-specific CXCL12 deficiency in mice limits arterial thrombosis by affecting thrombus growth and stability without increasing tail bleeding time. Accordingly, neointimal lesion formation after carotid artery injury was attenuated in these mice. Mechanistically, CXCL12 activated via CXCR4 a signaling cascade involving Bruton's tyrosine kinase (Btk) that led to integrin αIIbβ3 activation, platelet aggregation, and granule release. The heterodimeric interaction between CXCL12 and CCL5 can inhibit CXCL12-mediated effects as mimicked by CCL5-derived peptides such as [VREY]4. An improved variant of this peptide, i[VREY]4, binds to CXCL12 in a complex with CXCR4 on the surface of activated platelets, thereby inhibiting Btk activation and preventing platelet CXCL12-dependent arterial thrombosis. In contrast to standard antiplatelet therapies such as aspirin or P2Y12 inhibition, i[VREY]4 reduced CXCL12-induced platelet aggregation and yet did not prolong in vitro bleeding time. We provide evidence that platelet-derived CXCL12 is involved in arterial thrombosis and can be specifically targeted by peptides that harbor potential therapeutic value against atherothrombosis.
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