title: Premature senescence of endothelial cells upon chronic exposure to TNFα can be prevented by N-acetyl cysteine and plumericin.
abstract: Cellular senescence is characterized by a permanent cell-cycle arrest and a pro-inflammatory secretory phenotype, and can be induced by a variety of stimuli, including ionizing radiation, oxidative stress, and inflammation. In endothelial cells, this phenomenon might contribute to vascular disease. Plasma levels of the inflammatory cytokine tumor necrosis factor alpha (TNFα) are increased in age-related and chronic conditions such as atherosclerosis, rheumatoid arthritis, psoriasis, and Crohn's disease. Although TNFα is a known activator of the central inflammatory mediator NF-κB, and can induce the intracellular generation of reactive oxygen species (ROS), the question whether TNFα can induce senescence has not been answered conclusively. Here, we investigated the effect of prolonged TNFα exposure on the fate of endothelial cells and found that such treatment induced premature senescence. Induction of endothelial senescence was prevented by the anti-oxidant N-acetyl cysteine, as well as by plumericin and PHA-408, inhibitors of the NF-κB pathway. Our results indicated that prolonged TNFα exposure could have detrimental consequences to endothelial cells by causing senescence and, therefore, chronically increased TNFα levels might possibly contribute to the pathology of chronic inflammatory diseases by driving premature endothelial senescence.
authors.affiliation: Department of Vascular Biology and Thrombosis Research, Center for Physiology and Pharmacology, Medical University of Vienna, 1090 Vienna, Austria.|Department of Zoology, University of Sargodha, 40100 Sargodha Pakistan.
authors.forename: Shafaat Y
authors.initials: SY
authors.lastname: Khan
authors.affiliation: Department of Vascular Biology and Thrombosis Research, Center for Physiology and Pharmacology, Medical University of Vienna, 1090 Vienna, Austria.
authors.forename: Ezzat M
authors.initials: EM
authors.lastname: Awad
authors.affiliation: Department of Vascular Biology and Thrombosis Research, Center for Physiology and Pharmacology, Medical University of Vienna, 1090 Vienna, Austria.
authors.forename: Andre
authors.initials: A
authors.lastname: Oszwald
authors.affiliation: King's British Heart Foundation Centre, King's College London, London SE5 9NU, UK.
authors.forename: Manuel
authors.initials: M
authors.lastname: Mayr
authors.affiliation: King's British Heart Foundation Centre, King's College London, London SE5 9NU, UK.
authors.forename: Xiaoke
authors.initials: X
authors.lastname: Yin
authors.affiliation: Institute of Pharmacy/Pharmacognosy and Center for Molecular Biosciences Innsbruck (CMBI), University of Innsbruck, 6020 Innsbruck, Austria.
authors.forename: Birgit
authors.initials: B
authors.lastname: Waltenberger
authors.affiliation: Institute of Pharmacy/Pharmacognosy and Center for Molecular Biosciences Innsbruck (CMBI), University of Innsbruck, 6020 Innsbruck, Austria.
authors.forename: Hermann
authors.initials: H
authors.lastname: Stuppner
authors.affiliation: Karl Landsteiner Institute for Cell-based Therapy in Gynecology, 2100 Korneuburg, Austria.
authors.forename: Markus
authors.initials: M
authors.lastname: Lipovac
authors.affiliation: Department of Vascular Biology and Thrombosis Research, Center for Physiology and Pharmacology, Medical University of Vienna, 1090 Vienna, Austria.
authors.forename: Pavel
authors.initials: P
authors.lastname: Uhrin
authors.affiliation: Department of Vascular Biology and Thrombosis Research, Center for Physiology and Pharmacology, Medical University of Vienna, 1090 Vienna, Austria.
authors.forename: Johannes M
authors.initials: JM
authors.lastname: Breuss
mesh_terms: D000111:Acetylcysteine / Q000494:pharmacology*; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D016922:Cellular Senescence / Q000187:drug effects*; D042783:Endothelial Cells / Q000187:drug effects* / Q000378:metabolism; D016166:Free Radical Scavengers / Q000494:pharmacology*; D006801:Humans; D007249:Inflammation / Q000139:chemically induced; D016328:NF-kappa B / Q000378:metabolism; D010641:Phenotype; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
chemical_list: D016166:Free Radical Scavengers; D016328:NF-kappa B; D017382:Reactive Oxygen Species; D014409:Tumor Necrosis Factor-alpha; D000111:Acetylcysteine