Apolipoprotein A-IV binds αIIbβ3 integrin and inhibits thrombosis

• Published in: Nature communications Vol. 9; no. 1; pp. 3608 - 18
• Main Authors: Xu, Xiaohong Ruby, Wang, Yiming, Adili, Reheman, Ju, Lining, Spring, Christopher M., Jin, Joseph Wuxun, Yang, Hong, Neves, Miguel A. D., Chen, Pingguo, Yang, Yan, Lei, Xi, Chen, Yunfeng, Gallant, Reid C., Xu, Miao, Zhang, Hailong, Song, Jina, Ke, Peifeng, Zhang, Dan, Carrim, Naadiya, Yu, Si-Yang, Zhu, Guangheng, She, Yi-Min, Cyr, Terry, Fu, Wenbin, Liu, Guoqing, Connelly, Philip W., Rand, Margaret L., Adeli, Khosrow, Freedman, John, Lee, Jeffrey E., Tso, Patrick, Marchese, Patrizia, Davidson, W. Sean, Jackson, Shaun P., Zhu, Cheng, Ruggeri, Zaverio M., Ni, Heyu
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 06.09.2018; Nature Publishing Group; Nature Portfolio
• Subjects: 13/31; 38/70; 631/443/592/1339; 631/443/592/75/593/567; 64/110; 64/60; 82/29; 82/58; 82/80; 82/83; 9/10; 96/63; Adult; Agglomeration; Animals; Apolipoprotein A; Apolipoproteins; Apolipoproteins A - genetics; Apolipoproteins A - metabolism; Apolipoproteins A - pharmacology; Aspartic Acid - metabolism; Beads; Binding; Binding Sites; Blood plasma; C-Terminus; Cardiovascular diseases; Cerebral infarction; Circadian Rhythm - physiology; Circadian rhythms; Disease Models, Animal; Health risk assessment; Heart diseases; Hemostasis; Hemostatics; Humanities and Social Sciences; Humans; Hyperactivity; Ligands; Lipid metabolism; Metabolism; Mice, Inbred C57BL; Mice, Transgenic; Molecular interactions; multidisciplinary; Myocardial infarction; N-Terminus; Plasma levels; Platelet aggregation; Platelet Aggregation - drug effects; Platelet Aggregation Inhibitors - pharmacology; Platelet Glycoprotein GPIIb-IIIa Complex - metabolism; Platelets; Postprandial Period; Recombinant Proteins - genetics; Recombinant Proteins - metabolism; Recombinant Proteins - pharmacology; Science; Science (multidisciplinary); Thromboembolism; Thrombosis; Thrombosis - drug therapy; Thrombosis - metabolism
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-018-05806-0

Platelet αIIbβ3 integrin and its ligands are essential for thrombosis and hemostasis, and play key roles in myocardial infarction and stroke. Here we show that apolipoprotein A-IV (apoA-IV) can be isolated from human blood plasma using platelet β3 integrin-coated beads. Binding of apoA-IV to platelets requires activation of αIIbβ3 integrin, and the direct apoA-IV-αIIbβ3 interaction can be detected using a single-molecule Biomembrane Force Probe. We identify that aspartic acids 5 and 13 at the N-terminus of apoA-IV are required for binding to αIIbβ3 integrin, which is additionally modulated by apoA-IV C-terminus via intra-molecular interactions. ApoA-IV inhibits platelet aggregation and postprandial platelet hyperactivity. Human apoA-IV plasma levels show a circadian rhythm that negatively correlates with platelet aggregation and cardiovascular events. Thus, we identify apoA-IV as a novel ligand of αIIbβ3 integrin and an endogenous inhibitor of thrombosis, establishing a link between lipoprotein metabolism and cardiovascular diseases. Activation of integrin αIIbβ3 at the surface of platelets is required for their aggregation and for thrombus formation. Here Xu et al. identify apolipoprotein A-IV as a novel ligand for platelet αIIbβ3 integrin, and find it inhibits platelet aggregation and thrombosis.