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). METHODS AND 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.
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). METHODS AND 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.
Authors: Manojkumar Valiyaveettil; Niladri Kar; Mohammad Z Ashraf; Tatiana V Byzova; Maria Febbraio; Eugene A Podrez Journal: Blood Date: 2007-11-09 Impact factor: 22.113
Authors: Long Sheng Lu; Li Man Hung; Chang Hui Liao; Chau Chung Wu; Ming Jai Su Journal: Naunyn Schmiedebergs Arch Pharmacol Date: 2007-04-21 Impact factor: 3.000
Authors: Martin Berger; Katie Wraith; Casey Woodward; Ahmed Aburima; Zaher Raslan; Matthew S Hindle; Julia Moellmann; Maria Febbraio; Khalid M Naseem Journal: Platelets Date: 2018-05-07 Impact factor: 3.862
Authors: Jan Seifert; Hendrik von Eysmondt; Madhumita Chatterjee; Meinrad Gawaz; Tilman E Schäffer Journal: Cells Date: 2021-10-28 Impact factor: 6.600