Apolipoprotein A-IV binds αIIbβ3 integrin and inhibits thrombosis

Nat Commun. 2018 Sep 6;9(1):3608. 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Animals
  • Apolipoproteins A / genetics
  • Apolipoproteins A / metabolism*
  • Apolipoproteins A / pharmacology
  • Aspartic Acid / metabolism
  • Binding Sites
  • Circadian Rhythm / physiology
  • Disease Models, Animal
  • Humans
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Platelet Aggregation / drug effects
  • Platelet Aggregation Inhibitors / pharmacology
  • Platelet Glycoprotein GPIIb-IIIa Complex / metabolism*
  • Postprandial Period
  • Recombinant Proteins / genetics
  • Recombinant Proteins / metabolism
  • Recombinant Proteins / pharmacology
  • Thrombosis / drug therapy
  • Thrombosis / metabolism*


  • Apolipoproteins A
  • Platelet Aggregation Inhibitors
  • Platelet Glycoprotein GPIIb-IIIa Complex
  • Recombinant Proteins
  • apolipoprotein A-IV
  • Aspartic Acid