Journal
ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY
Volume 24, Issue 7, Pages 1309-1314Publisher
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1161/01.ATV.0000131784.50633.4f
Keywords
acute coronary syndromes; plaque erosion; myeloperoxidase; apoptosis; oxidative stress; endothelial cells; tissue factor
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Funding
- NHLBI NIH HHS [HL-56985, HL-34636] Funding Source: Medline
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Objective - Superficial erosion of coronary plaques due to endothelial loss causes acute coronary syndromes (ACS). Macrophages at erosive sites of human coronary atheroma present myeloperoxidase (MPO), an enzyme that produces hypochlorous acid (HOCl). Methods and Results - Activated MPO-positive macrophages or exogenous HOCl promoted detachment of endothelial cells (EC) from Matrigel substrata in vitro. Pathophysiologically relevant concentrations of HOCl caused EC death in a concentration-dependent manner: HOCl (20 to 50 mumol/L) induced rapid shrinkage of EC with nuclear condensation and disruption of EC monolayers, whereas concentrations >100 mumol/L immediately induced blebbing of the EC plasma membrane without shrinkage. HOCl ( 30 to 50 mumol/L) also induced caspase-3 activation, poly (ADP-ribose) polymerase degradation, and DNA laddering in EC. HOCl rapidly decreased endothelial Bcl-2 and induced cytochrome-C release, indicating that HOCl activates apoptotic EC death, partially via mitochondrial damage. Increased intracellular glutathione (GSH) levels after treatment with GSH monoethyl ester (GSH-MEE) attenuated HOCl-induced EC apoptosis. Sublethal concentrations of HOCl (1.0 to 15 mumol/L) increased tissue factor in EC and GSH-MEE treatment limited this effect of HOCl. Conclusions - HOCl can provoke EC death and desquamation by either apoptotic or oncotic cell-death pathways, and sublethal concentrations of HOCl can increase endothelial tissue factor. These results show that MPO-positive macrophage-derived HOCl in the subendothelium of atheromata may participate in ACS by promoting superficial erosion and increasing thrombogenicity.
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