title: Inhibition of lipopolysaccharide-induced apoptosis by cilostazol in human umbilical vein endothelial cells.
abstract: This work describes the pharmacological inhibition by cilostazol and its metabolites, OPC-13015 and OPC-13213, of the apoptosis in the human umbilical vein endothelial cells (HUVECs) damaged by lipopolysaccharide (LPS) in comparison with its analog, cilostamide. Cilostazol and OPC-31213 caused a significant suppression of cell death induced by LPS (1 microg/ml) in a concentration-dependent manner but a modest suppression by cilostamide and OPC-13015. These compounds potently inhibited the 5,5-dimethyl-1-pyrroline-1-oxide (DMPO)/(*)OH adduct formation and significantly reduced the increased intracellular reactive oxygen species (ROS) and tumor necrosis factor-alpha (TNF-alpha) production induced by LPS (1 microg/ml). An apoptotic death of HUVECs by 1 microg/ml LPS (DNA ladders on electrophoresis) was strongly suppressed by all these compounds. Incubation with LPS caused a marked decrease in Bcl-2 protein, which was significantly reversed by cilostazol and its analogs. The greatly increased Bax protein expression and cytochrome c release by LPS were, in contrast, suppressed by cilostazol and, to a lesser degree, by others. In conclusion, cilostazol and its analogs exert a strong protection against apoptotic cell death by scavenging hydroxyl radicals and intracellular ROS with reduction in TNF-alpha formation and by increasing Bcl-2 protein expression and decreasing Bax protein and cytochrome c release.
authors.affiliation: Department of Pharmacology, College of Medicine, and Research Institute of Genetic Engineering, Pusan National University, Pusan, Korea.
authors.forename: Ki Young
authors.initials: KY
authors.lastname: Kim
authors.forename: Hwa Kyoung
authors.initials: HK
authors.lastname: Shin
authors.forename: Jae Moon
authors.initials: JM
authors.lastname: Choi
authors.forename: Ki Whan
authors.initials: KW
authors.lastname: Hong
mesh_terms: D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000037:antagonists & inhibitors; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D002478:Cells, Cultured; D000077407:Cilostazol; D054684:Cyclic Nucleotide Phosphodiesterases, Type 3; D003574:Cytochrome c Group / Q000378:metabolism; D053938:DNA Fragmentation / Q000187:drug effects; D004578:Electron Spin Resonance Spectroscopy; D004730:Endothelium, Vascular / Q000166:cytology* / Q000187:drug effects; D016166:Free Radical Scavengers / Q000494:pharmacology; D006801:Humans; D017665:Hydroxyl Radical / Q000378:metabolism; D008070:Lipopolysaccharides / Q000037:antagonists & inhibitors* / Q000633:toxicity; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis; D017382:Reactive Oxygen Species / Q000378:metabolism; D013777:Tetrazoles / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis; D014471:Umbilical Veins / Q000166:cytology / Q000187:drug effects; D051028:bcl-2-Associated X Protein
chemical_list: C494826:BAX protein, human; D003574:Cytochrome c Group; D016166:Free Radical Scavengers; D008070:Lipopolysaccharides; D010726:Phosphodiesterase Inhibitors; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D017382:Reactive Oxygen Species; D013777:Tetrazoles; D014409:Tumor Necrosis Factor-alpha; D051028:bcl-2-Associated X Protein; D017665:Hydroxyl Radical; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D054684:Cyclic Nucleotide Phosphodiesterases, Type 3; D000077407:Cilostazol