Hypochlorous Acid, a Macrophage Product, Induces Endothelial Apoptosis and Tissue Factor Expression

Abstract

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.... 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.