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Platelet activation by the apoB/E receptor-binding domain of LDL
A M Relou1, G Gorter, H J M van Rijn
1Department of Haematology, University Medical Center Utrecht, The Netherlands. i.relou@lab.azu.nl
Low density lipoprotein (LDL) increases the sensitivity of human platelets for agonists by activating p38MAPK. Antibody 4G3 disturbs apoB100 binding to the classical apoB/E receptor and inhibits LDL-induced p38MAPK activation, whereas an antibody against a distal domain on apoB 100 has no effect. Peptide RLTRKRGLKLA mimics the binding domain of apoB 100 called the B-site and activates platelet p38MAPK. Activation by B-site peptide is dose-dependent, transient and followed by desensitization, in accordance with receptor-mediated signalling. A scrambled peptide and a partially homologous peptide RKLRKRLLRDA mimicking the apoB/E receptor binding site of apoE in high density lipoprotein (HDL) also activate p38MAPK albeit 40% weaker, but an uncharged peptide lacks p38MAPK activating capacity. LDL and B-site peptide bind to the same binding sites and initiate similar signalling to p38MAPK and cytosolic phospholipase A2. Thus, LDL and to a lesser extent HDL activate platelets via specific domains in the protein moiety that recognize receptors of the LDL receptor family.
Low density lipoprotein (LDL) increases the sensitivity of human platelets for agonists by activating p38MAPK. Antibody 4G3 disturbs apoB100 binding to the classical apoB/E receptor and inhibits LDL-induced p38MAPK activation, whereas an antibody against a distal domain on apoB 100 has no effect. Peptide RLTRKRGLKLA mimics the binding domain of apoB 100 called the B-site and activates platelet p38MAPK. Activation by B-site peptide is dose-dependent, transient and followed by desensitization, in accordance with receptor-mediated signalling. A scrambled peptide and a partially homologous peptide RKLRKRLLRDA mimicking the apoB/E receptor binding site of apoE in high density lipoprotein (HDL) also activate p38MAPK albeit 40% weaker, but an uncharged peptide lacks p38MAPK activating capacity. LDL and B-site peptide bind to the same binding sites and initiate similar signalling to p38MAPK and cytosolic phospholipase A2. Thus, LDL and to a lesser extent HDL activate platelets via specific domains in the protein moiety that recognize receptors of the LDL receptor family.