Apolipoprotein A-IV: Novel αIIbβ3 Integrin Ligand and Endogenous Thrombotic Inhibitor

Apolipoprotein A-IV (apoA-IV) is a lipid binding protein that is synthesized in the small intestine during lipid absorption. Although reports suggest that plasma apoA-IV levels are inversely correlated with coronary artery disease (CAD), its role in platelet function and thrombosis, the major cause of CAD, is unknown. Here, I demonstrated that apoA-IV inhibited platelet aggregation and thrombus growth - with enhanced inhibition at higher shear rates - while lacking apoA-IV resulted in accelerated thrombosis. Using intravital microscopy, I found a unique pattern of apoA-IV deposition on thrombi. Through collaboration, we found the direct binding force between apoA-IV and platelet αIIbβ3 integrin. ApoA-IV competitively inhibited pro-thrombotic fibrinogen binding to αIIbβ3. We demonstrated apoA-IV N-terminal aspartic acids (D5 and D13) are required for αIIbβ3 binding and the inhibition of platelet aggregation and thrombosis. Thus, apoA-IV is a novel αIIbβ3 ligand and endogenous thrombotic inhibitor, representing the novel mechanisms of prevention for CAD.M.Sc.2017-12-22 00:00:0