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Pranlukast attenuates ischemia-like injury in endothelial cells via inhibiting reactive oxygen species production and nuclear factor-kappaB activation.

Abstract
The anti-inflammatory effects of pranlukast, an antagonist of cysteinyl leukotriene receptor 1, may be rendered not only by antileukotriene activity but also by other pharmacological activities. Previous studies indicate that pranlukast reduces ischemic tissue injury partially through decreasing vascular permeability, but its effect on ischemic injury in endothelial cells is not known. Thus, in this study, we investigated the effect of pranlukast on ischemia-like injury induced by oxygen-glucose deprivation (OGD) in EA.hy926 cells, a human endothelial cell line, and the possible mechanisms. We found that cell viability was reduced, lactate dehydrogenase release was increased 4-8 hours after OGD, and necrosis was induced 8 hours after OGD. Production of reactive oxygen species (ROS) increased by 211%, 176%, and 128%, respectively, 0.5, 1, and 2 hours after OGD. Nuclear factor-kappaB (NF-kappaB) was translocated to the nuclei 4-8 hours after OGD. Pranlukast ameliorated the reduced viability, the increased lactate dehydrogenase release, and necrosis after OGD. It also reduced ROS production and inhibited NF-kappaB nuclear translocation after OGD. The ROS scavenger, edaravone, inhibited OGD-induced nuclear translocation of NF-kappaB as well. Edaravone and pyrrolidine dithiocarbamate (a specific NF-kappaB inhibitor) protected endothelial cells from the OGD-induced injury. However, zileuton, a 5-lipoxygenase inhibitor, did not affect the cell injury, ROS production, and NF-kappaB nuclear translocation after OGD. The exogenous leukotriene D4 did not induce cell injury, ROS production, and NF-kappaB translocation. Thus, we conclude that pranlukast protects endothelial cells from ischemia-like injury via decreasing ROS production and inhibiting NF-kappaB activation, which is leukotriene independent.
AuthorsSan-Hua Fang, Yu-Mei Yuan, Fang Peng, Cheng-Tan Li, Li-Hui Zhang, Yun-Bi Lu, Wei-Ping Zhang, Er-Qing Wei
JournalJournal of cardiovascular pharmacology (J Cardiovasc Pharmacol) Vol. 53 Issue 1 Pg. 77-85 (Jan 2009) ISSN: 1533-4023 [Electronic] United States
PMID19129732 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Chromones
  • Leukotriene Antagonists
  • Leukotrienes
  • NF-kappa B
  • Reactive Oxygen Species
  • Leukotriene D4
  • Arachidonate 5-Lipoxygenase
  • Glucose
  • Oxygen
  • pranlukast
Topics
  • Arachidonate 5-Lipoxygenase (genetics, metabolism, pharmacology)
  • Cell Line
  • Cell Nucleus (genetics, metabolism)
  • Cell Survival (drug effects, genetics)
  • Chromones
  • Endothelial Cells (metabolism)
  • Glucose (genetics, metabolism, pharmacology)
  • Humans
  • Ischemia (genetics, metabolism)
  • Leukotriene Antagonists (metabolism, pharmacology)
  • Leukotriene D4 (genetics, metabolism, pharmacology)
  • Leukotrienes (genetics, metabolism, pharmacology)
  • NF-kappa B (antagonists & inhibitors, genetics, metabolism)
  • Necrosis (genetics, metabolism)
  • Oxygen (metabolism, pharmacology)
  • Reactive Oxygen Species (metabolism, pharmacology)

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