title: Functional inhibition of Ras by S-trans,trans-farnesyl thiosalicylic acid attenuates atherosclerosis in apolipoprotein E knockout mice.
abstract: BACKGROUND
  Atherosclerosis is a multifactorial disorder involving inflammatory processes. These responses are associated with robust activation of signaling cascades by diverse cell surface receptors in a variety of cell types. The processes that are involved in atherosclerosis would likely require intact Ras pathways, which play a key role in the control of cell growth, differentiation, and apoptosis.
  
  
  RESULTS
  We examined whether the Ras inhibitor farnesyl thiosalicylic acid (FTS) can suppress atherogenesis in the apolipoprotein E-deficient mouse model. Mice were treated with FTS or a control regimen 3 times weekly for 6 weeks and fed a normal chow diet. Two additional groups included FTS-treated and control-treated mice that were fed a high-fat diet for 10 weeks. FTS reduced both fatty streaks and advanced lesions compared with the control treatment. Ras inhibition in vivo was evidenced by the reduced content of the active form of Ras (Ras-GTP) in aortas of FTS-treated mice. Splenocytes from the FTS-treated versus control mice exhibited reduced proliferation to oxidized LDL (OxLDL) but not to concanavalin A. IgG anti-OxLDL antibody levels were reduced in FTS-treated mice compared with controls. Whereas no effect of FTS was evident on plaque T lymphocyte and macrophage content, lesional vascular cell adhesion molecule-1 and nuclear factor-kappaB expression were considerably reduced compared with controls.
  
  
  CONCLUSIONS
  FTS suppressed atherosclerotic plaques in apolipoprotein E-deficient mice, providing a useful tool for research in atherosclerosis.
authors.affiliation: Department of Cardiology and the Cardiovascular Research Laboratory, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel.
authors.forename: Jacob
authors.initials: J
authors.lastname: George
authors.forename: Arnon
authors.initials: A
authors.lastname: Afek
authors.forename: Pnina
authors.initials: P
authors.lastname: Keren
authors.forename: Itzhak
authors.initials: I
authors.lastname: Herz
authors.forename: Iris
authors.initials: I
authors.lastname: Goldberg
authors.forename: Roni
authors.initials: R
authors.lastname: Haklai
authors.forename: Yoel
authors.initials: Y
authors.lastname: Kloog
authors.forename: Gad
authors.initials: G
authors.lastname: Keren
mesh_terms: D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D001057:Apolipoproteins E / Q000172:deficiency* / Q000235:genetics; D001161:Arteriosclerosis / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D001323:Autoantibodies / Q000097:blood; D002455:Cell Division / Q000187:drug effects / Q000276:immunology; D002478:Cells, Cultured; D002784:Cholesterol / Q000097:blood; D004041:Dietary Fats; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005204:Farnesol / Q000031:analogs & derivatives* / Q000494:pharmacology*; D007274:Injections, Intraperitoneal; D008077:Lipoproteins, LDL / Q000276:immunology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016328:NF-kappa B / Q000378:metabolism; D012459:Salicylates / Q000494:pharmacology*; D013154:Spleen / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D016896:Treatment Outcome; D014280:Triglycerides / Q000097:blood; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism; D018631:ras Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D001057:Apolipoproteins E; D001323:Autoantibodies; D004041:Dietary Fats; D004791:Enzyme Inhibitors; D008077:Lipoproteins, LDL; D016328:NF-kappa B; D012459:Salicylates; D014280:Triglycerides; D019010:Vascular Cell Adhesion Molecule-1; C093323:farnesylthiosalicylic acid; C099252:oxidized low density lipoprotein; D005204:Farnesol; D002784:Cholesterol; D018631:ras Proteins