title: PARP inhibition in atherosclerosis and its effects on dendritic cells, T cells and auto-antibody levels.
abstract: OBJECTIVE
  Atherosclerosis is a chronic inflammatory process. Poly(ADP-ribose) polymerase-1 (PARP), a nuclear enzyme linked to DNA repair, has been shown to be involved in atherogenesis; however, the effects on dendritic cells, T cells and serum auto-antibody levels are not fully understood.
  
  
  METHODS
  Male Apoe-/- mice on a western diet were treated with the PARP inhibitor INO-1001 (n = 15), while the control group (n = 15) received 5% glucose solution for 10 weeks.
  
  
  RESULTS
  Inhibition of PARP markedly reduced atherosclerotic lesion development (p = 0.001). Immunohistochemistry and mRNA analysis revealed a reduced inflammatory compound inside the lesion. Focusing on dendritic cells, INO-1001 reduced number of cells (p = 0.04), grade of activation, represented by Il12 (p = 0.04) and Cd83 (p = 0.03), and grade of attraction, represented by Mip3α (p = 0.02) in the plaque. Furthermore, INO-1001 decreased number of T lymphocyte (p = 0.003) in the lesion and grade of activation after stimulation with oxLDL in vitro. Moreover, serum IgM antibody levels to oxLDL were significantly lower in INO-1001 treated mice (p = 0.03).
  
  
  CONCLUSIONS
  Functional blockade of PARP by INO-1001 reduces atherosclerotic lesion development. The anti-atherogenic effect is beside already known mechanisms also moderated due to modulation of DC and T cell invasion and activation, DC attraction as well as IgM antibody levels to oxLDL.
authors.affiliation: Department of Cardiology, Angiology and Pneumology, Medical Clinic III, University Hospital Heidelberg, INF 410, 69120 Heidelberg, Germany. Christian.Erbel@med.uni-heidelberg.de
authors.forename: Christian
authors.initials: C
authors.lastname: Erbel
authors.forename: J
authors.initials: J
authors.lastname: Achenbach
authors.forename: M
authors.initials: M
authors.lastname: Akhavanpoor
authors.forename: T J
authors.initials: TJ
authors.lastname: Dengler
authors.forename: F
authors.initials: F
authors.lastname: Lasitschka
authors.forename: C A
authors.initials: CA
authors.lastname: Gleissner
authors.forename: F
authors.initials: F
authors.lastname: Bea
authors.forename: H A
authors.initials: HA
authors.lastname: Katus
authors.forename: G
authors.initials: G
authors.lastname: Szabo
mesh_terms: D000818:Animals; D001057:Apolipoproteins E / Q000235:genetics; D050197:Atherosclerosis / Q000201:enzymology* / Q000235:genetics / Q000378:metabolism; D001323:Autoantibodies / Q000737:chemistry*; D004260:DNA Repair; D003713:Dendritic Cells / Q000166:cytology / Q000201:enzymology*; D007150:Immunohistochemistry / Q000379:methods; D007249:Inflammation; D008077:Lipoproteins, LDL / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases / Q000235:genetics; D012313:RNA / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013154:Spleen / Q000378:metabolism; D013601:T-Lymphocytes / Q000201:enzymology* / Q000378:metabolism
chemical_list: D001057:Apolipoproteins E; D001323:Autoantibodies; D008077:Lipoproteins, LDL; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D012313:RNA; D011065:Poly(ADP-ribose) Polymerases