LDLs increase the exposure of fibrinogen binding sites on platelets and secretion of dense granules.
Because previous studies show that lipoproteins affect platelet aggregation, we studied the effect of low-density lipoprotein (LDL) and high-density lipoprotein (HDL) on the binding of fibrinogen, which mediates platelet-platelet contact. Neither LDL nor HDL induced 125I-fibrinogen binding at concentrations up to 2 g protein/L. In contrast, platelets stimulated with 10 mumol/L ADP bound 63 734 +/- 2453 molecules of fibrinogen per platelet. A 5-minute preincubation with LDL (0.5 to 2 g/L protein) induced a dose-dependent increase to 91 307 +/- 2164 molecules of fibrinogen per platelet at 1.5 g/L, which is in the range found after optimal stimulation with alpha-thrombin. The increased fibrinogen binding in the presence of LDL resulted in faster aggregation with a 16% increase in single platelet disappearance and a faster optical aggregation at 5 mumol/L ADP and 1.5 g protein/L LDL. Inhibition of prostaglandin G2/H2-thromboxane A2 formation with indomethacin (30 mumol/L) did not change the stimulation by LDL. In contrast, modification of lysine residues of LDL, which is known to prevent specific binding to platelets, completely abolished the effect of LDL. Under the same conditions HDL did not change fibrinogen binding or aggregation. LDL also enhanced alpha-thrombin-induced [14C]serotonin secretion, but this property was not affected by lysine modification of LDL. These data indicate that LDL enhances platelet aggregation by stimulating the mechanisms that control exposure of fibrinogen binding sites on the glycoprotein IIB/IIIA complex via a mechanism that differs from the effect of LDL on secretion.
van Willigen
G
G
Department of Haematology, University Hospital, Utrecht, The Netherlands.
Gorter
G
G
Akkerman
J W
JW
D000244:Adenosine Diphosphate / Q000494:pharmacology; D001665:Binding Sites; D001792:Blood Platelets / Q000187:drug effects / Q000378:metabolism*; D003594:Cytoplasmic Granules / Q000502:physiology*; D005340:Fibrinogen / Q000378:metabolism*; D006801:Humans; D007213:Indomethacin / Q000494:pharmacology; D008075:Lipoproteins, HDL / Q000494:pharmacology; D008077:Lipoproteins, LDL / Q000737:chemistry / Q000494:pharmacology*; D008239:Lysine / Q000737:chemistry; D010974:Platelet Aggregation / Q000187:drug effects; D010980:Platelet Membrane Glycoproteins / Q000378:metabolism; D012701:Serotonin / Q000378:metabolism; D013917:Thrombin / Q000494:pharmacology
D008075:Lipoproteins, HDL; D008077:Lipoproteins, LDL; D010980:Platelet Membrane Glycoproteins; D012701:Serotonin; D000244:Adenosine Diphosphate; D005340:Fibrinogen; D013917:Thrombin; D008239:Lysine; D007213:Indomethacin