Hypochlorous acid, a macrophage product, induces endothelial apoptosis and tissue factor expression: involvement of myeloperoxidase-mediated oxidant in plaque erosion and thrombogenesis.
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).


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 micromol/L) induced rapid shrinkage of EC with nuclear condensation and disruption of EC monolayers, whereas concentrations >100 micromol/L immediately induced blebbing of the EC plasma membrane without shrinkage. HOCl (30 to 50 micromol/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 micromol/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.
Sugiyama
Seigo
S
Leducq Center for Cardiovascular Research, Brigham and Women's Hospital, Harvard Medical School, Boston, Mass 02115, USA.
Kugiyama
Kiyotaka
K
Aikawa
Masanori
M
Nakamura
Shinichi
S
Ogawa
Hisao
H
Libby
Peter
P
D000975:Antioxidants / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D002462:Cell Membrane / Q000187:drug effects; D002478:Cells, Cultured / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D006801:Humans; D006997:Hypochlorous Acid / Q000378:metabolism / Q000494:pharmacology*; D008264:Macrophages / Q000187:drug effects / Q000201:enzymology / Q000502:physiology*; D009000:Monocytes / Q000201:enzymology; D009504:Neutrophils / Q000201:enzymology; D009195:Peroxidase / Q000502:physiology*; D011725:Pyridines / Q000494:pharmacology; D012501:Saphenous Vein / Q000166:cytology; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D013925:Thromboplastin / Q000378:metabolism*
D000975:Antioxidants; D011725:Pyridines; D006997:Hypochlorous Acid; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D013925:Thromboplastin; C086276:cerivastatin; D009195:Peroxidase; D013755:Tetradecanoylphorbol Acetate