title: Cocaine induces apoptosis in human coronary artery endothelial cells.
abstract: This study was designed to determine the direct cytotoxic effect of cocaine on human coronary artery endothelial cells (HCAECs). Cocaine treatment of cultured HCAECs induced a time- and dose-dependent increase in apoptotic cell death in HCAECs. Cocaine-induced surface exposure of phosphatidylserine in HCAECs was seen as early as at 6 h. With prolonged treatment < or =72 h, cocaine (10-500 microM) produced a dose-dependent increase in apoptosis in the cells. Corresponding DNA fragmentation induced by cocaine was demonstrated in situ by terminal deoxynucleotidyl transferase (Tdt) UTP nick end-labeling TUNEL assay and by electrophoresis of labeled DNA fragments, showing the characteristic apoptotic ladders. Both caspase-9 (Z-LEHD-FMK) and caspase-3 (Ac-DEVD-CHO) inhibitors blocked cocaine-induced apoptosis. In addition, cyclosporin A inhibited cocaine-induced apoptosis in a concentration-dependent manner with a median inhibitory concentration (IC50) of 0.3 microM. The maximum of 62% inhibition was obtained with 3 microM cyclosporin A. Cocaine-induced apoptosis also was blocked by naloxone and nifedipine in a dose-dependent manner. These findings suggest that cocaine induces apoptosis in cultured HCAECs, which may be mediated by opioid receptors. The release of cytochrome c from the mitochondria and its subsequent activation of caspase-9 and caspase-3 may play a key role in cocaine-induced apoptosis.
authors.affiliation: Department of Pharmacology, Loma Linda University School of Medicine, California 92350, USA.
authors.forename: J
authors.initials: J
authors.lastname: He
authors.forename: Y
authors.initials: Y
authors.lastname: Xiao
authors.forename: L
authors.initials: L
authors.lastname: Zhang
mesh_terms: D017209:Apoptosis; D061945:Caspase Inhibitors; D002478:Cells, Cultured; D003042:Cocaine / Q000494:pharmacology*; D003331:Coronary Vessels / Q000166:cytology; D016572:Cyclosporine / Q000494:pharmacology; D004347:Drug Interactions; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D009270:Naloxone / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000494:pharmacology; D009543:Nifedipine / Q000494:pharmacology; D014662:Vasoconstrictor Agents / Q000494:pharmacology*; D014665:Vasodilator Agents / Q000494:pharmacology
chemical_list: D061945:Caspase Inhibitors; D004791:Enzyme Inhibitors; D009292:Narcotic Antagonists; D014662:Vasoconstrictor Agents; D014665:Vasodilator Agents; D009270:Naloxone; D016572:Cyclosporine; D003042:Cocaine; D009543:Nifedipine