title: Simvastatin inhibits human saphenous vein neointima formation via inhibition of smooth muscle cell proliferation and migration.
abstract: OBJECTIVE
  Migration and proliferation of vascular smooth muscle cells (SMCs) contributes to intimal hyperplasia in saphenous vein (SV) bypass grafts, which leads to patency-threatening stenosis. Evidence for the involvement of basement membrane-degrading matrix metalloproteinases (MMPs) and growth factors in mediating SMC migration and proliferation has been presented in a number of in vitro and in vivo models. 3-Hydroxy-3 methylglutaryl CoA reductase inhibitors (statins) are widely used in patients with atherosclerosis and are claimed to have additional effects beyond cholesterol reduction. We therefore examined the effects of simvastatin, a commonly prescribed statin, on the proliferation and migration of cultured human SV SMC and on neointima formation and MMP activity in human SV organ cultures. To clarify its mode of action, we studied in parallel the effects of a specific MMP inhibitor, marimastat.
  
  
  METHODS
  Human SV specimens were obtained from patients who underwent coronary artery bypass grafting, and were cultured for 14 days in the presence of three concentrations of simvastatin and subsequently processed for measurement of MMP activity and neointimal thickness measurements. Cultured SV SMCs were used to construct growth curves in the presence of 10% fetal calf serum or 10% fetal calf serum supplemented with simvastatin or marimastat. Migration through a Matrigel basement-membrane matrix (invasion) was quantified with modified Boyden chambers.
  
  
  RESULTS
  Simvastatin dose dependently reduced neointima formation (P =.004) in association with reduced MMP-9 activity (P =.03). SMC proliferation and invasion also were inhibited with simvastatin (P <.007 and P <.009, respectively). Marimastat dose dependently inhibited SMC invasion (P <.001) but importantly had no effect on SMC proliferation (P >.36).
  
  
  CONCLUSIONS
  For effective control of neointimal development in vivo, a pharmacologic strategy should inhibit both SMC migration and proliferation. The ancillary properties of 3-Hydroxy-3 methylglutaryl CoA reductase inhibitors typified by simvastatin may be important in this regard.
authors.affiliation: Integrated Molecular Cardiology Group, Institute for Cardiovascular Research, University of Leeds, United Kingdom. medkep@leeda.ac.uk
authors.forename: Karen E
authors.initials: KE
authors.lastname: Porter
authors.forename: Jagjeeth
authors.initials: J
authors.lastname: Naik
authors.forename: Neil A
authors.initials: NA
authors.lastname: Turner
authors.forename: Timothy
authors.initials: T
authors.lastname: Dickinson
authors.forename: Matthew M
authors.initials: MM
authors.lastname: Thompson
authors.forename: Nicholas J M
authors.initials: NJ
authors.lastname: London
mesh_terms: D002464:Cell Migration Inhibition; D004305:Dose-Response Relationship, Drug; D004341:Drug Evaluation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000008:administration & dosage*; D020778:Matrix Metalloproteinase 2 / Q000187:drug effects; D020780:Matrix Metalloproteinase 9 / Q000187:drug effects; D008798:Mevalonic Acid / Q000008:administration & dosage; D009131:Muscle, Smooth, Vascular / Q000166:cytology* / Q000187:drug effects*; D012501:Saphenous Vein / Q000187:drug effects*; D019821:Simvastatin / Q000008:administration & dosage*; D017539:Tunica Intima / Q000166:cytology* / Q000187:drug effects*
chemical_list: D004791:Enzyme Inhibitors; D006877:Hydroxamic Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D019821:Simvastatin; C100342:marimastat; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9; D008798:Mevalonic Acid