title: Aspirin attenuates vinorelbine-induced endothelial inflammation via modulating SIRT1/AMPK axis.
abstract: Vinorelbine (VNR), a semisynthetic vinca alkaloid acquired from vinblastine, is frequently used as the candidate for intervention of solid tumors. Nevertheless, VNR-caused endothelial injuries may lead a mitigative effect of clinical treatment efficiency. A growing body of evidence reveals that aspirin is a potent antioxidant and anti-inflammation drug. We investigated whether aspirin attenuate VNR-induced endothelial dysfunction. Human endothelial cells (EA.hy 926) were treated with VNR to cause endothelial inflammation. Western blotting, ROS assay, ELISA were used to confirm the anti-inflammatory effect of aspirin. We confirmed that VNR suppresses SIRT1 expression, reduced LKB1 and AMPK phosphorylation as well as enriched PKC activation in treated endothelial cells. Furthermore, the membrane translocation assay displayed that the levels of NADPH oxidase subunits p47phox and Rac-1 in membrane fractions of endothelial cells were higher in cells that had been treated with VNR for than in untreated cells. We corroborated that treatment of Aspirin significantly diminishes VNR-repressed SIRT1, LKB1 and AMPK phosphorylation and VNR-promoted NADPH oxidase activation, however, those findings were vanished by SIRT1 and AMPK siRNAs. Our data also shown that Aspirin represses VNR-activated TGF-beta-activated kinase-1 (TAK1) activation, inhibited the interaction of TAK1/TAK-binding protein1 (TAB1), suppressed NF-kappa B activation and pro-inflammatory cytokine secretion. We demonstrated a novel connection between VNR-caused oxidative damages and endothelial dysfunction, and provide further insight into the protective effects of aspirin in VNR-caused endothelial dysfunction.
authors.affiliation: Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan.
authors.forename: Kun-Ling
authors.initials: KL
authors.lastname: Tsai
authors.affiliation: Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan; Division of Cardiology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan.
authors.forename: Po-Hsun
authors.initials: PH
authors.lastname: Huang
authors.affiliation: Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan; Department of Physical Medicine and Rehabilitation, Taipei, Taiwan.
authors.forename: Chung-Lan
authors.initials: CL
authors.lastname: Kao
authors.affiliation: Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan; Division of Cardiology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan.
authors.forename: Hsin-Bang
authors.initials: HB
authors.lastname: Leu
authors.affiliation: Division of Cardiology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan; Institute of Pharmacology, National Yang-Ming University, Taipei, Taiwan.
authors.forename: Yung-Hsin
authors.initials: YH
authors.lastname: Cheng
authors.affiliation: Division of Cardiology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan; Institute of Pharmacology, National Yang-Ming University, Taipei, Taiwan; Department of Medical Research and Education, Taipei Veterans General Hospital, Taipei, Taiwan.
authors.forename: Yi-Wen
authors.initials: YW
authors.lastname: Liao
authors.affiliation: Division of Cardiology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan; Institute of Pharmacology, National Yang-Ming University, Taipei, Taiwan; Department of Medical Research and Education, Taipei Veterans General Hospital, Taipei, Taiwan.
authors.forename: Yi-Ping
authors.initials: YP
authors.lastname: Yang
authors.affiliation: Division of Cardiology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan; Institute of Pharmacology, National Yang-Ming University, Taipei, Taiwan; Department of Medical Research and Education, Taipei Veterans General Hospital, Taipei, Taiwan.
authors.forename: Yueh
authors.initials: Y
authors.lastname: Chien
authors.affiliation: Department of Emergency Medicine, National Yang-Ming University, Taipei, Taiwan.
authors.forename: Chien-Ying
authors.initials: CY
authors.lastname: Wang
authors.affiliation: Department of Surgery, National Yang-Ming University Hospital, Taipei, Taiwan.
authors.forename: Chen-Yuan
authors.initials: CY
authors.lastname: Hsiao
authors.affiliation: Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan; Division of Cardiology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan; Institute of Pharmacology, National Yang-Ming University, Taipei, Taiwan; Department of Medical Research and Education, Taipei Veterans General Hospital, Taipei, Taiwan. Electronic address: shchiou@vghtpe.gov.tw.
authors.forename: Shih-Hwa
authors.initials: SH
authors.lastname: Chiou
authors.affiliation: Division of Cardiology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan; Institute of Pharmacology, National Yang-Ming University, Taipei, Taiwan; Department of Medical Research and Education, Taipei Veterans General Hospital, Taipei, Taiwan.
authors.forename: Jaw-Wen
authors.initials: JW
authors.lastname: Chen
authors.affiliation: Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan; Division of Cardiology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan; Department of Medical Research and Education, Taipei Veterans General Hospital, Taipei, Taiwan. Electronic address: sjlin@vghtpe.gov.tw.
authors.forename: Shing-Jong
authors.initials: SJ
authors.lastname: Lin
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D000972:Antineoplastic Agents, Phytogenic / Q000633:toxicity; D001241:Aspirin / Q000494:pharmacology*; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D007249:Inflammation / Q000378:metabolism; D056564:Sirtuin 1 / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D014747:Vinblastine / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors / Q000633:toxicity; D000077235:Vinorelbine
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D000972:Antineoplastic Agents, Phytogenic; D014747:Vinblastine; D055372:AMP-Activated Protein Kinases; C447939:SIRT1 protein, human; D056564:Sirtuin 1; D000077235:Vinorelbine; D001241:Aspirin
keywords: AMPK; Inflammation; Reactive oxygen species; SIRT1; Vinorelbine