Effect of oxidation on the platelet-activating properties of low-density lipoprotein.
OBJECTIVE
Because of the large variation in oxidizing procedures and susceptibility to oxidation of low-density lipoprotein (LDL) and the lack in quantification of LDL oxidation, the role of oxidation in LDL-platelet contact has remained elusive. This study aims to compare platelet activation by native LDL (nLDL) and oxidized LDL (oxLDL).


RESULTS
After isolation, nLDL was dialyzed against FeSO4 to obtain LDL oxidized to well-defined extents varying between 0% and >60%. The oxLDL preparations were characterized with respect to their platelet-activating properties. An increase in LDL oxidation enhances platelet activation via 2 independent pathways, 1 signaling via p38(MAPK) phosphorylation and 1 via Ca2+ mobilization. Between 0% and 15% oxidation, the p38(MAPK) route enhances fibrinogen binding induced by thrombin receptor (PAR-1)-activating peptide (TRAP), and signaling via Ca2+ is absent. At >30% oxidation, p38(MAPK) signaling increases further and is accompanied by Ca2+ mobilization and platelet aggregation in the absence of a second agonist. Despite the increase in p38(MAPK) signaling, synergism with TRAP disappears and oxLDL becomes an inhibitor of fibrinogen binding. Inhibition is accompanied by binding of oxLDL to the scavenger receptor CD36, which is associated with the fibrinogen receptor, alpha(IIb)beta3.


CONCLUSIONS
At >30% oxidation, LDL interferes with ligand binding to integrin alpha(IIb)beta3, thereby attenuating platelet functions.
Korporaal
Suzanne J A
SJ
Thrombosis and Haemostasis Laboratory, Department of Haematology, University Medical Center Utrecht, Utrecht, The Netherlands.
Gorter
Gertie
G
van Rijn
Herman J M
HJ
Akkerman
Jan-Willem N
JW
D001792:Blood Platelets / Q000378:metabolism*; D018955:CD36 Antigens / Q000378:metabolism; D020013:Calcium Signaling / Q000502:physiology; D000242:Cyclic AMP / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D039001:Integrin alpha Chains / Q000378:metabolism; D039641:Integrin beta Chains / Q000378:metabolism; D008024:Ligands; D008077:Lipoproteins, LDL / Q000378:metabolism*; D020935:MAP Kinase Signaling System / Q000502:physiology; D010084:Oxidation-Reduction; D010974:Platelet Aggregation / Q000502:physiology*; D011485:Protein Binding / Q000502:physiology; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D018955:CD36 Antigens; D039001:Integrin alpha Chains; D039641:Integrin beta Chains; D008024:Ligands; D008077:Lipoproteins, LDL; C099252:oxidized low density lipoprotein; D000242:Cyclic AMP; D048051:p38 Mitogen-Activated Protein Kinases