Published online before print May 13, 2004, doi: 10.1161/01.ATV.0000131784.50633.4f
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© 2004 American Heart Association, Inc.
Thrombosis |
Hypochlorous Acid, a Macrophage Product, Induces Endothelial Apoptosis and Tissue Factor Expression
Involvement of Myeloperoxidase-Mediated Oxidant in Plaque Erosion and Thrombogenesis
From the Leducq Center for Cardiovascular Research (S.S., M.A., P.L.), Brigham and Women’s Hospital, Harvard Medical School, Boston, Mass; the Department of Cardiovascular Medicine (S.S., S.N., H.O.), Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan; and the Second Department of Internal Medicine (K.K.), Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, Yamanashi, Japan.
Correspondence to Peter Libby, MD, Brigham and Women’s Hospital, 77 Avenue Louis Pasteur, NRB 741, Boston, MA 02115. E-mail plibby{at}rics.bwh.harvard.edu
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 µmol/L) induced rapid shrinkage of EC with nuclear condensation and disruption of EC monolayers, whereas concentrations >100 µmol/L immediately induced blebbing of the EC plasma membrane without shrinkage. HOCl (30 to 50 µmol/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 µmol/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.
Coronary erosion causes acute coronary syndromes (ACS). Macrophages at sites of ulceration in human atheromata can contain myeloperoxidase (MPO) that generates hypochlorous acid (HOCl). HOCl provokes endothelial cell death by either apoptosis or oncosis and increases tissue factor. MPO-positive macrophage-derived HOCl may participate in ACS by promoting erosion and increasing thrombogenicity.
Key Words: acute coronary syndromes • plaque erosion • myeloperoxidase • apoptosis • oxidative stress • endothelial cells • tissue factor
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