Apolipoprotein A-IV binds αIIbβ3 integrin and inhibits thrombosis

Xiaohong Ruby Xu, Yiming Wang, Reheman Adili, Lining Ju, Christopher M. Spring, Joseph Wuxun Jin, Hong Yang, Miguel A.D. Neves, Pingguo Chen, Yan Yang, Xi Lei, Yunfeng Chen, Reid C. Gallant, Miao Xu, Hailong Zhang, Jina Song, Peifeng Ke, Dan Zhang, Naadiya Carrim, Si Yang YuGuangheng Zhu, Yi Min She, Terry Cyr, Wenbin Fu, Guoqing Liu, Philip W. Connelly, Margaret L. Rand, Khosrow Adeli, John Freedman, Jeffrey E. Lee, Patrick Tso, Patrizia Marchese, W. Sean Davidson, Shaun P. Jackson, Cheng Zhu, Zaverio M. Ruggeri, Heyu Ni

Research output: Contribution to journalArticlepeer-review

79 Scopus citations

Abstract

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.

Original languageEnglish (US)
Article number3608
JournalNature communications
Volume9
Issue number1
DOIs
StatePublished - Dec 1 2018
Externally publishedYes

ASJC Scopus subject areas

  • General Chemistry
  • General Biochemistry, Genetics and Molecular Biology
  • General Physics and Astronomy

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