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; Heyu Ni

doi:10.1038/s41467-018-05806-0

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 journal › Article › peer-review

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 language	English (US)
Article number	3608
Journal	Nature communications
Volume	9
Issue number	1
DOIs	https://doi.org/10.1038/s41467-018-05806-0
State	Published - Dec 1 2018
Externally published	Yes

ASJC Scopus subject areas

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

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10.1038/s41467-018-05806-0

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Xu, X. R., Wang, Y., Adili, R., Ju, L., Spring, C. M., Jin, J. W., Yang, H., Neves, M. A. D., Chen, P., Yang, Y., Lei, X., Chen, Y., Gallant, R. C., Xu, M., Zhang, H., Song, J., Ke, P., Zhang, D., Carrim, N., ... Ni, H. (2018). Apolipoprotein A-IV binds αIIbβ3 integrin and inhibits thrombosis. Nature communications, 9(1), Article 3608. https://doi.org/10.1038/s41467-018-05806-0

Xu, XR, Wang, Y, Adili, R, Ju, L, Spring, CM, Jin, JW, Yang, H, Neves, MAD, Chen, P, Yang, Y, Lei, X, Chen, Y, Gallant, RC, Xu, M, Zhang, H, Song, J, Ke, P, Zhang, D, Carrim, N, Yu, SY, Zhu, G, She, YM, Cyr, T, Fu, W, Liu, G, Connelly, PW, Rand, ML, Adeli, K, Freedman, J, Lee, JE, Tso, P, Marchese, P, Davidson, WS, Jackson, SP, Zhu, C, Ruggeri, ZM & Ni, H 2018, 'Apolipoprotein A-IV binds αIIbβ3 integrin and inhibits thrombosis', Nature communications, vol. 9, no. 1, 3608. https://doi.org/10.1038/s41467-018-05806-0

@article{a7a12fb6ff3d43b0afafb0e488c978b7,

title = "Apolipoprotein A-IV binds αIIbβ3 integrin and inhibits thrombosis",

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.",

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

note = "Publisher Copyright: {\textcopyright} 2018, The Author(s).",

year = "2018",

month = dec,

day = "1",

doi = "10.1038/s41467-018-05806-0",

language = "English (US)",

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T1 - Apolipoprotein A-IV binds αIIbβ3 integrin and inhibits thrombosis

AU - Xu, Xiaohong Ruby

AU - Wang, Yiming

AU - Adili, Reheman

AU - Ju, Lining

AU - Spring, Christopher M.

AU - Jin, Joseph Wuxun

AU - Yang, Hong

AU - Neves, Miguel A.D.

AU - Chen, Pingguo

AU - Yang, Yan

AU - Lei, Xi

AU - Chen, Yunfeng

AU - Gallant, Reid C.

AU - Xu, Miao

AU - Zhang, Hailong

AU - Song, Jina

AU - Ke, Peifeng

AU - Zhang, Dan

AU - Carrim, Naadiya

AU - Yu, Si Yang

AU - Zhu, Guangheng

AU - She, Yi Min

AU - Cyr, Terry

AU - Fu, Wenbin

AU - Liu, Guoqing

AU - Connelly, Philip W.

AU - Rand, Margaret L.

AU - Adeli, Khosrow

AU - Freedman, John

AU - Lee, Jeffrey E.

AU - Tso, Patrick

AU - Marchese, Patrizia

AU - Davidson, W. Sean

AU - Jackson, Shaun P.

AU - Zhu, Cheng

AU - Ruggeri, Zaverio M.

AU - Ni, Heyu

PY - 2018/12/1

Y1 - 2018/12/1

N2 - 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.

AB - 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.

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SN - 2041-1723

VL - 9

JO - Nature communications

JF - Nature communications

IS - 1

M1 - 3608

ER -

Apolipoprotein A-IV binds αIIbβ3 integrin and inhibits thrombosis

Abstract

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