title: Beneficial effects of quinoline-3-carboxamide (ABR-215757) on atherosclerotic plaque morphology in S100A12 transgenic ApoE null mice.
abstract: OBJECTIVE
  There is an emerging widespread interest in the role of damage-associated molecular pattern molecules (DAMP) S100A8, S100A9 and S100A12 in cardiovascular and other diseases. In this study we tested the efficacy of ABR-215757, a S100 protein binding immuno-modulatory compound to stabilize atherosclerosis in transgenic ApoE null mice that express the human pro-inflammatory S100A12 protein within the smooth muscle cell (SM22α-S100A12).
  
  
  METHODS
  Twelve-week old S100A12 transgenic/ApoE(-/-) and WT/ApoE(-/-) mice were treated with ABR-21575 for 5 weeks and were analyzed 4 month later.
  
  
  RESULTS
  Surface plasmon resonance analysis demonstrated that S100A12 interacts with ABR-215757 in a zinc dependent manner in vitro. In vivo, ABR-215757 administration reduced features of advanced plaque morphology resulting in smaller necrotic cores, diminished intimal and medial vascular calcification, and reduced amount of infiltrating inflammatory cells. ABR-215757 normalized aortic expression of RAGE protein and normalized experimentally-induced delayed hypersensitivity. The effect of ABR-215757 was more prominent in ApoE(-/-) mice expressing S100A12 than in ApoE(-/-) animals lacking expression of human S100A12 protein.
  
  
  CONCLUSIONS
  Our data suggest that S100A12 is important for progression of atherosclerosis and can be targeted by the small molecule ABR-215757. The specific binding of quinoline-3-carboxamides to S100A12 attenuates S100A12-mediated features of accelerated murine atherosclerosis.
authors.affiliation: Department of Medicine, Section of Cardiology, The University of Chicago, IL, USA.
authors.forename: Ling
authors.initials: L
authors.lastname: Yan
authors.forename: Per
authors.initials: P
authors.lastname: Bjork
authors.forename: Radu
authors.initials: R
authors.lastname: Butuc
authors.forename: Joseph
authors.initials: J
authors.lastname: Gawdzik
authors.forename: Judy
authors.initials: J
authors.lastname: Earley
authors.forename: Gene
authors.initials: G
authors.lastname: Kim
authors.forename: Marion A
authors.initials: MA
authors.lastname: Hofmann Bowman
mesh_terms: D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects / Q000473:pathology / Q000502:physiology; D001057:Apolipoproteins E / Q000235:genetics*; D050197:Atherosclerosis / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D040502:Calgranulin B / Q000378:metabolism; D004195:Disease Models, Animal; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D058226:Plaque, Atherosclerotic / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D011485:Protein Binding / Q000187:drug effects / Q000502:physiology; D011804:Quinolines / Q000494:pharmacology*; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000235:genetics; D011994:Recombinant Proteins / Q000235:genetics; D009418:S100 Proteins / Q000235:genetics* / Q000378:metabolism; D000067616:S100A12 Protein; D014657:Vasculitis / Q000188:drug therapy / Q000235:genetics / Q000473:pathology; D015032:Zinc / Q000378:metabolism
chemical_list: D001057:Apolipoproteins E; D040502:Calgranulin B; D007166:Immunosuppressive Agents; D011804:Quinolines; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic; D011994:Recombinant Proteins; D009418:S100 Proteins; D000067616:S100A12 Protein; C090441:S100A12 protein, human; C573440:paquinimod; D015032:Zinc