title: Prevention of transplant coronary artery disease by prenylation inhibitors.
abstract: BACKGROUND
  In this study we systematically dissect the prenylation pathway to better define the mechanism behind statin inhibition in chronic allograft rejection in heart transplants, or transplant coronary artery disease (TCAD).
  
  
  METHODS
  Utilizing a murine heterotopic heart transplant model, animals received daily treatments of either statin or selective isoprenoid blockade inhibitors to block the four major downstream branches of the mevalonate pathway. TCAD was assessed by morphometric analysis at Day 52. Graft-infiltrating cells, cytokine production, smooth muscle cell proliferation and migration and endothelial cell MHC II expression were detected on Day 7.
  
  
  RESULTS
  Atorvastatin and two prenylation inhibitors, NE-10790 and manumycin A, significantly reduced TCAD lesions compared with untreated animals. Perillyl alcohol treatment resulted in a trend toward decreased luminal narrowing. Finally, zaragozic acid (cholesterol blockade only) did not alter TCAD severity. Statins and prenylation inhibitors reduced inflammatory cell allograft recruitment, but did not always correlate with TCAD reduction. Cytokine production was decreased in recipient spleens in all treatment groups. Both in vitro and in vivo IFN-γ-stimulated MHC II expression was decreased in a dose-dependent manner in the atorvastatin, perillyl alcohol and NE-10790 groups. In vitro smooth muscle cell proliferation was decreased in all treatment groups. Finally, in vitro smooth muscle cell migration was decreased in the atorvastatin, NE-10790 and manumycin A groups only.
  
  
  CONCLUSIONS
  FPT and GGPT-2 (inhibition) are the key enzymes in the HGM-CoA reductase pathway and most influential in TCAD prevention. TCAD reduction is most closely related to smooth muscle cell migration, but not its anti-inflammatory properties.
authors: Department of Cardiothoracic Surgery, Stanford University School of Medicine, Stanford, California 94305, USA.
authors: William
authors: W
authors: Stein
authors: Sonja
authors: S
authors: Schrepfer
authors: Satoshi
authors: S
authors: Itoh
authors: Naoyuki
authors: N
authors: Kimura
authors: Jeffrey
authors: J
authors: Velotta
authors: Owen
authors: O
authors: Palmer
authors: Jason
authors: J
authors: Bartos
authors: Xi
authors: X
authors: Wang
authors: Robert C
authors: RC
authors: Robbins
authors: Michael P
authors: MP
authors: Fischbein
mesh_terms: D000818:Animals; D000069059:Atorvastatin; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology; D003324:Coronary Artery Disease / Q000209:etiology / Q000473:pathology / Q000517:prevention & control*; D004164:Diphosphonates / Q000494:pharmacology*; D005802:Genes, MHC Class II; D006085:Graft Survival; D016027:Heart Transplantation / Q000009:adverse effects; D006538:Heptanoic Acids / Q000494:pharmacology*; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D007111:Immunity, Cellular; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008954:Models, Biological; D009130:Muscle, Smooth / Q000166:cytology; D011090:Polyenes / Q000494:pharmacology*; D053284:Polyunsaturated Alkamides / Q000494:pharmacology*; D054876:Prenylation / Q000187:drug effects*; D011725:Pyridines / Q000494:pharmacology*; D011758:Pyrroles / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D016042:Transplantation, Heterotopic; D014233:Tricarboxylic Acids / Q000494:pharmacology
chemical_list: C410028:2-(3-pyridinyl)-1-hydroxyethylidene-1,1-phosphonocarboxylic acid; D019086:Bridged Bicyclo Compounds, Heterocyclic; D004164:Diphosphonates; D006538:Heptanoic Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D011090:Polyenes; D053284:Polyunsaturated Alkamides; D011725:Pyridines; D011758:Pyrroles; D014233:Tricarboxylic Acids; C075117:squalestatin 1; D000069059:Atorvastatin; C054474:manumycin