title: LDL oxidized by hypochlorous acid causes irreversible platelet aggregation when combined with low levels of ADP, thrombin, epinephrine, or macrophage-derived chemokine (CCL22).
abstract: The in vitro oxidation of low-density lipoprotein (LDL) by hypochlorous acid produces a modified form (HOCl-LDL) capable of stimulating platelet function. We now report that HOCl-LDL is highly effective at inducing platelet function, causing stable aggregation and alpha-granule secretion. Such stimulation depended on the presence of low levels of primary agonists such as adenosine diphosphate (ADP) and thrombin, or others like epinephrine (EPI) and macrophage-derived chemokine (MDC, CCL22). Agonist levels, which by themselves induced little or reversible aggregation, caused strong stable aggregation when combined with low levels of HOCl-LDL. Platelet activation by HOCl-LDL and ADP (1 microM) caused P-selectin (CD62P) exposure, without serotonin or adenosine triphosphate (ATP) secretion. Intracellular calcium levels rose slowly (from 100 to 200 nM) in response to HOCl-LDL alone and rapidly when combined with ADP to about 300 nM. p38 mitogen-activated protein kinase (MAPK) became phosphorylated in response to HOCl-LDL alone. This phosphorylation was not blocked by the protein kinase C (PKC) inhibitor bisindolylmaleimide, which reduced the extent of aggregation and calcium increase. However, the p38 MAPK inhibitor SB203580 blocked platelet aggregation and phosphorylation of p38 MAPK. These findings suggest that HOCl-LDL exposed during atherosclerotic plaque rupture, coupled with low levels of primary agonists, can rapidly induce extensive and stable thrombus formation.
authors.affiliation: Department of Biochemistry and Molecular Genetics, University of Virginia Health Sciences Center, Charlottesville, VA 22908, USA.
authors.forename: Leon G
authors.initials: LG
authors.lastname: Coleman
authors.forename: Renata K
authors.initials: RK
authors.lastname: Polanowska-Grabowska
authors.forename: Marek
authors.initials: M
authors.lastname: Marcinkiewicz
authors.forename: Adrian R L
authors.initials: AR
authors.lastname: Gear
mesh_terms: D000244:Adenosine Diphosphate / Q000494:pharmacology*; D000255:Adenosine Triphosphate / Q000378:metabolism; D001792:Blood Platelets / Q000166:cytology / Q000187:drug effects; D002118:Calcium / Q000378:metabolism; D048429:Cell Size / Q000187:drug effects; D054422:Chemokine CCL22; D019742:Chemokines, CC / Q000494:pharmacology*; D008078:Cholesterol, LDL / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004837:Epinephrine / Q000494:pharmacology; D005340:Fibrinogen / Q000494:pharmacology; D006490:Hemostatics / Q000494:pharmacology*; D006801:Humans; D006997:Hypochlorous Acid / Q000494:pharmacology; D007093:Imidazoles / Q000494:pharmacology; D007211:Indoles / Q000494:pharmacology; D008077:Lipoproteins, LDL / Q000378:metabolism*; D008301:Maleimides / Q000494:pharmacology; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors; D010084:Oxidation-Reduction / Q000187:drug effects; D019007:P-Selectin / Q000378:metabolism; D010974:Platelet Aggregation / Q000187:drug effects*; D011493:Protein Kinase C / Q000037:antagonists & inhibitors; D011725:Pyridines / Q000494:pharmacology; D022142:Secretory Vesicles / Q000187:drug effects / Q000378:metabolism; D012701:Serotonin / Q000378:metabolism; D013566:Sympathomimetics / Q000494:pharmacology; D013917:Thrombin / Q000494:pharmacology*; D048051:p38 Mitogen-Activated Protein Kinases
chemical_list: C515482:CCL22 protein, human; D054422:Chemokine CCL22; D019742:Chemokines, CC; D008078:Cholesterol, LDL; D004791:Enzyme Inhibitors; D006490:Hemostatics; D007093:Imidazoles; D007211:Indoles; D008077:Lipoproteins, LDL; D008301:Maleimides; D019007:P-Selectin; D011725:Pyridines; D013566:Sympathomimetics; C099252:oxidized low density lipoprotein; D012701:Serotonin; D000244:Adenosine Diphosphate; D006997:Hypochlorous Acid; D000255:Adenosine Triphosphate; D005340:Fibrinogen; D011493:Protein Kinase C; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D013917:Thrombin; C088060:bisindolylmaleimide; C093642:SB 203580; D002118:Calcium; D004837:Epinephrine