title: Poly(ADP-ribose) polymerase 1 inhibition protects against low shear stress induced inflammation.
abstract: BACKGROUND
  Atherosclerosis begins as local inflammation of vessels at sites of disturbed flow, where low shear stress (LSS) leads to mechanical irritation and plaque development and progression. Nuclear enzyme poly(ADP-ribose) polymerase 1 (PARP-1) is associated with the inflammation response during atherosclerosis. We investigated the role and underlying mechanism of PARP-1 in LSS-induced inflammation in human umbilical vein endothelial cells (HUVECs).
  
  
  RESULTS
  HUVECs were simulated by LSS (0.4Pa). PARP-1 expression was inhibited by ABT888 or siRNA. The inducible nitric oxide synthase (iNOS) and intercellular adhesion molecular-1 (ICAM-1) expression was regulated by LSS in a time dependent manner. LSS could increase superoxide production and 3-nitrotyrosine formation. LSS induced DNA damage as assessed by H2A.X phosphorylation and comet assay. Compared with cells under static, LSS increased PARP-1 expression and PAR formation via MEK/ERK signaling pathway. PARP-1 inhibition increased Sirt1 activity through an increased intracellular nicotinamide adenine dinucleotide (NAD(+)) level. Moreover, PARP-1 inhibition attenuated LSS-induced iNOS and ICAM-1 upregulation by inhibiting nuclear factor kappa B (NF-κB) nuclear translocation and activity, with a reduced NF-κB phosphorylation.
  
  
  CONCLUSIONS
  LSS induced oxidative damage and PARP-1 activation via MEK/ERK pathway. PARP-1 inhibition restored Sirt1 activity by increasing NAD(+) level and decreased iNOS and ICAM-1 expression by inhibiting NF-κB nuclear translocation and activity as well as NF-κB phosphorylation. PARP-1 played a fundamental role in LSS induced inflammation. Inhibition of PARP-1 might be a mechanism for treatment of inflammation response during atherosclerosis.
authors.affiliation: Qilu Hospital of Shandong University, Jinan, Shandong, China.
authors.forename: Wei-dong
authors.initials: WD
authors.lastname: Qin
authors.forename: Shu-jian
authors.initials: SJ
authors.lastname: Wei
authors.forename: Xu-ping
authors.initials: XP
authors.lastname: Wang
authors.forename: Juan
authors.initials: J
authors.lastname: Wang
authors.forename: Wen-ke
authors.initials: WK
authors.lastname: Wang
authors.forename: Fuqiang
authors.initials: F
authors.lastname: Liu
authors.forename: Lei
authors.initials: L
authors.lastname: Gong
authors.forename: Fei
authors.initials: F
authors.lastname: Yan
authors.forename: Yun
authors.initials: Y
authors.lastname: Zhang
authors.forename: Mingxiang
authors.initials: M
authors.lastname: Zhang
mesh_terms: D002478:Cells, Cultured; D019610:Cytoprotection / Q000187:drug effects* / Q000235:genetics; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D006801:Humans; D007249:Inflammation / Q000209:etiology / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control*; D018836:Inflammation Mediators / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000235:genetics / Q000378:metabolism; D000071137:Poly (ADP-Ribose) Polymerase-1; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000494:pharmacology*; D033081:Shear Strength / Q000187:drug effects / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D013314:Stress, Mechanical; D013997:Time Factors
chemical_list: D004791:Enzyme Inhibitors; D018836:Inflammation Mediators; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D034741:RNA, Small Interfering; C496319:NOS2 protein, human; D052247:Nitric Oxide Synthase Type II; C499320:PARP1 protein, human; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases