title: Sphingosylphosphorylcholine induces apoptosis of endothelial cells through reactive oxygen species-mediated activation of ERK.
abstract: Sphingosylphosphorylcholine (SPC) produces reactive oxygen species (ROS) in MS1 pancreatic islet endothelial cells. In the present study, we explored the physiological significance of the SPC-induced ROS generation in endothelial cells. SPC induced cell death of MS1 cells at higher than 10 microM concentration through a caspase-3-dependent pathway. SPC treatment induced sustained activation of an extracellular signal-regulated kinase (ERK), in contrast to transient activation of ERK in response to platelet-derived growth factor (PDGF)-BB, which stimulated proliferation of MS1 cells. Both the SPC-induced cell death and ERK activation were abolished by pretreatment of the cells with the MEK inhibitor U0126 or by overexpression of a dominant negative mutant of MEK1 (DN-MEK1). Pretreatment of the cells with N-acetylcysteine, an antioxidant, completely prevented the SPC-induced ROS generation, apoptosis, and ERK activation, whereas the ROS generation was not abrogated by treatment with U0126. Consistent with these results, SPC induced cell death of human umbilical vein endothelial cells (HUVECs) through ROS-mediated activation of ERK. These results suggest that the SPC-induced generation of ROS plays a crucial role in the cell death of endothelial cells through ERK-dependent pathway.
authors.affiliation: Medical Research Center for Ischemic Tissue Regeneration and Medical Research Institute, College of Medicine, Pusan National University, Busan 602-739, Republic of Korea.
authors.forename: Eun Su
authors.initials: ES
authors.lastname: Jeon
authors.forename: Mi Jeong
authors.initials: MJ
authors.lastname: Lee
authors.forename: Sang-Min
authors.initials: SM
authors.lastname: Sung
authors.forename: Jae Ho
authors.initials: JH
authors.lastname: Kim
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D002070:Butadienes / Q000494:pharmacology; D053148:Caspase 3 / Q000378:metabolism; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D005434:Flow Cytometry; D006801:Humans; D020287:In Situ Nick-End Labeling; D051379:Mice; D009570:Nitriles / Q000494:pharmacology; D010767:Phosphorylcholine / Q000031:analogs & derivatives* / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000494:pharmacology; D014162:Transfection
chemical_list: D002070:Butadienes; D004791:Enzyme Inhibitors; D009570:Nitriles; D017382:Reactive Oxygen Species; C113580:U 0126; C005356:sphingosine phosphorylcholine; D010767:Phosphorylcholine; D048049:Extracellular Signal-Regulated MAP Kinases; D053148:Caspase 3; D013110:Sphingosine