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(Arteriosclerosis, Thrombosis, and Vascular Biology. 1999;19:239-247.)
© 1999 American Heart Association, Inc.

Original Contributions

Low-Density Lipoprotein Enhances Platelet Secretion Via Integrin-_IIbß₃–Mediated Signaling

Christian M. Hackeng; Merei Huigsloot; Marc W. Pladet; H. Karel Nieuwenhuis; Herman J. M. van Rijn; Jan-Willem N. Akkerman

From the Departments of Clinical Chemistry (C.M.H., M.H., M.W.P., H.J.M.v.R.) and Haematology (C.M.H., M.H., H.K.N., J.-W.N.A.), University Hospital Utrecht, and Institute for Biomembranes, Utrecht University, Utrecht, The Netherlands.

Correspondence to Prof dr Jan-Willem N. Akkerman, Department of Haematology, University Hospital Utrecht, PO Box 85500, 3508 GA Utrecht, Heidelberglaan 100, 3584 CX Utrecht, The Netherlands. E-mail J.W.N.Akkerman{at}laboratory.azu.nl

Abstract—LDL is known to increase the sensitivity of human platelets for agonists and to induce aggregation and secretion independently at high concentrations, but its mechanism of action is largely obscure. To clarify how LDL increases platelet sensitivity, cells were incubated in lipoprotein-poor plasma and treated with collagen at a concentration that induced 20% secretion of ¹⁴C-serotonin. Preincubation with LDL (30 minutes at 37°C) enhanced secretion in a dose-dependent manner to 60±14% at a concentration of 2 g LDL protein/L. Similar stimulation by LDL was seen when secretion was induced by the thrombin receptor–activating peptide. This enhancement was strongly reduced (1) in the presence of monoclonal antibody PAC1 against activated _IIbß₃, a polyclonal antibody against _IIb, and in the presence of the fibrinogen peptides GRGDS and HHLGGAKQAGDV; (2) in _IIbß₃-deficient platelets; and (3) after dissociation of _IIbß₃. In contrast, binding of ¹²⁵I-LDL to normal platelets in the presence of PAC1, anti-_IIb, GRGDS, and HHLGGAKQAGDV, and to _IIbß₃-deficient platelets was normal. LDL increased the surface expression of fibrinogen in lipoprotein-poor plasma and fibrinogen-free medium, suggesting that extracellular and granular fibrinogen bind to _IIbß₃ after platelet-LDL interaction. Platelets deficient in fibrinogen (<0.5% of normal) or von Willebrand Factor (<1% of normal) but containing normal amounts of other ligands for _IIbß₃ preserved responsiveness to LDL, indicating that occupancy of _IIbß₃ was not restricted to fibrinogen. Inhibition of protein kinase C (bisindolylmaleimide) diminished fibrinogen binding and sensitization by LDL; inhibition of tyrosine kinases (herbimycin A) left fibrinogen binding unchanged but diminished sensitization by LDL. We conclude that an increased concentration of LDL, such as observed in homozygous familial hypercholesterolemia, sensitizes platelets to stimulation by collagen and thrombin receptor–activating peptide via ligand-induced outside-in signaling through integrin-_IIbß₃.

Key Words: lipoproteins • LDL • platelet activation • integrin _IIbß₃ • protein kinases • signal transduction

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