title: Farnesyltransferase inhibitor R115777 protects against vascular disease in uremic mice.
abstract: BACKGROUND
  Atherosclerosis and vascular calcification are major contributors to cardiovascular morbidity and mortality among chronic kidney disease patients. The mevalonate pathway may play a role in this vascular pathology. Farnesyltransferase inhibitors such as R115777 block one branch of mevalonate pathway. We studied the effects of farnesyltransferase inhibitor R115777 on vascular disease in apolipoprotein E deficient mice with chronic renal failure and on mineral deposition in vitro.
  
  
  RESULTS
  Female uremic and non-uremic apolipoprotein E deficient mice were randomly assigned to four groups and treated with either farnesyltransferase inhibitor R115777 or vehicle. Farnesyltransferase inhibitor R115777 inhibited protein prenylation in mice with chronic renal failure. It decreased aortic atheromatous lesion area and calcification in these animals, and reduced vascular nitrotyrosine expression and total collagen as well as collagen type I content. Proteomic analysis revealed that farnesyltransferase inhibitor corrected the chronic renal failure-associated increase in serum apolipoprotein IV and α globin, and the chronic renal failure-associated decrease in serum fetuin A. Farnesyltransferase inhibitor further inhibited type I collagen synthesis and reduced mineral deposition in vascular smooth muscle cells in vitro, probably involving Ras-Raf pathway.
  
  
  CONCLUSIONS
  We show for the first time that farnesyltransferase inhibition slows vascular disease progression in chronic renal failure by both indirect systemic and direct local actions. This beneficial effect was mediated via a reduction in oxidative stress and favorable changes in vasoprotective peptides.
authors.affiliation: Inserm Unit 1088, Amiens; University of Picardie Jules Verne and Amiens University Hospital, Amiens, France.
authors.forename: Igor G
authors.initials: IG
authors.lastname: Nikolov
authors.forename: Nobuhiko
authors.initials: N
authors.lastname: Joki
authors.forename: Antoine
authors.initials: A
authors.lastname: Galmiche
authors.forename: Thao
authors.initials: T
authors.lastname: Nguyen-Khoa
authors.forename: Ida Chiara
authors.initials: IC
authors.lastname: Guerrera
authors.forename: François
authors.initials: F
authors.lastname: Guillonneau
authors.forename: Ognen
authors.initials: O
authors.lastname: Ivanovski
authors.forename: Olivier
authors.initials: O
authors.lastname: Phan
authors.forename: Julien
authors.initials: J
authors.lastname: Maizel
authors.forename: Frédéric
authors.initials: F
authors.lastname: Marçon
authors.forename: Joyce
authors.initials: J
authors.lastname: Benchitrit
authors.forename: Anthony
authors.initials: A
authors.lastname: Lucas
authors.forename: Aleksander
authors.initials: A
authors.lastname: Edelman
authors.forename: Bernard
authors.initials: B
authors.lastname: Lacour
authors.forename: Tilman B
authors.initials: TB
authors.lastname: Drüeke
authors.forename: Ziad A
authors.initials: ZA
authors.lastname: Massy
mesh_terms: D000818:Animals; D001011:Aorta / Q000378:metabolism / Q000473:pathology; D001057:Apolipoproteins E / Q000235:genetics; D017209:Apoptosis; D050197:Atherosclerosis / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D001798:Blood Proteins / Q000032:analysis / Q000378:metabolism; D001835:Body Weight; D024042:Collagen Type I / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D051231:Farnesyltranstransferase / Q000037:antagonists & inhibitors*; D005260:Female; D007676:Kidney Failure, Chronic / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D008099:Liver / Q000378:metabolism; D008264:Macrophages / Q000473:pathology; D008798:Mevalonic Acid / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009131:Muscle, Smooth, Vascular / Q000378:metabolism / Q000473:pathology; D054876:Prenylation / Q000187:drug effects; D015363:Quinolones / Q000494:pharmacology*; D011897:Random Allocation; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D014443:Tyrosine / Q000031:analogs & derivatives / Q000378:metabolism; D014511:Uremia / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D061205:Vascular Calcification / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*
chemical_list: D001057:Apolipoproteins E; D001798:Blood Proteins; D024042:Collagen Type I; D004791:Enzyme Inhibitors; D015363:Quinolones; C002744:3-nitrotyrosine; D014443:Tyrosine; D051231:Farnesyltranstransferase; C402769:tipifarnib; D008798:Mevalonic Acid