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 Yu, Guangheng 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 and Heyu Ni ()
Additional contact information
Xiaohong Ruby Xu: University of Toronto
Yiming Wang: University of Toronto
Reheman Adili: St. Michael’s Hospital, and Toronto Platelet Immunobiology Group
Lining Ju: Georgia Institute of Technology
Christopher M. Spring: St. Michael’s Hospital, and Toronto Platelet Immunobiology Group
Joseph Wuxun Jin: St. Michael’s Hospital, and Toronto Platelet Immunobiology Group
Hong Yang: St. Michael’s Hospital, and Toronto Platelet Immunobiology Group
Miguel A. D. Neves: St. Michael’s Hospital, and Toronto Platelet Immunobiology Group
Pingguo Chen: St. Michael’s Hospital, and Toronto Platelet Immunobiology Group
Yan Yang: St. Michael’s Hospital, and Toronto Platelet Immunobiology Group
Xi Lei: St. Michael’s Hospital, and Toronto Platelet Immunobiology Group
Yunfeng Chen: Georgia Institute of Technology
Reid C. Gallant: University of Toronto
Miao Xu: University of Toronto
Hailong Zhang: St. Michael’s Hospital, and Toronto Platelet Immunobiology Group
Jina Song: St. Michael’s Hospital, and Toronto Platelet Immunobiology Group
Peifeng Ke: Guangzhou University of Chinese Medicine
Dan Zhang: St. Michael’s Hospital, and Toronto Platelet Immunobiology Group
Naadiya Carrim: St. Michael’s Hospital, and Toronto Platelet Immunobiology Group
Si-Yang Yu: St. Michael’s Hospital, and Toronto Platelet Immunobiology Group
Guangheng Zhu: St. Michael’s Hospital, and Toronto Platelet Immunobiology Group
Yi-Min She: Biologics and Genetic Therapies Directorate, HPFB, Health Canada
Terry Cyr: Biologics and Genetic Therapies Directorate, HPFB, Health Canada
Wenbin Fu: Department of Acupuncture and Moxibustion, Guangdong Provincial Hospital of Chinese Medicine
Guoqing Liu: Peking University Health Science Center
Philip W. Connelly: University of Toronto
Margaret L. Rand: University of Toronto
Khosrow Adeli: University of Toronto
John Freedman: University of Toronto
Jeffrey E. Lee: University of Toronto
Patrick Tso: University of Cincinnati
Patrizia Marchese: The Scripps Research Institute
W. Sean Davidson: University of Cincinnati
Shaun P. Jackson: The University of Sydney
Cheng Zhu: Georgia Institute of Technology
Zaverio M. Ruggeri: The Scripps Research Institute
Heyu Ni: University of Toronto

Nature Communications, 2018, vol. 9, issue 1, 1-18

Abstract: 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.

Date: 2018
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DOI: 10.1038/s41467-018-05806-0

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