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: England Nature Publishing Group 06.09.2018; Nature Publishing Group UK; Nature Portfolio
• Subjects: 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; Humans; Hyperactivity; Ligands; Lipid metabolism; Metabolism; Mice, Inbred C57BL; Mice, Transgenic; Molecular interactions; 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; 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.