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Blood, 15 July 2004, Vol. 104, No. 2, pp. 380-389.
Prepublished online as a Blood First Edition Paper on March 30, 2004; DOI 10.1182/blood-2003-08-2961.
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Submitted September 2, 2003
Accepted January 26, 2004
LDL oxidized by hypochlorous acid causes irreversible platelet aggregation when combined with low levels of ADP, thrombin, epinephrine or macrophage-derived chemokine (CCL22)
Leon G Coleman, Renata K Polanowska-Grabowska, Marek Marcinkiewicz, and Adrian R Gear*
Biochemistry and Molecular Genetics, University of Virginia, Charlottesville, VA, USA
* Corresponding author; email: alg4p{at}virginia.edu.
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  -granule secretion. Such stimulation depended on the presence of low levels of primary agonists such as 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 µM) caused P-selectin (CD62P) exposure, without serotonin or 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 MAPK became phosphorylated in response to HOCL-LDL alone. This phosphorylation was not blocked by the 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.
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