title: Fluvastatin prevents vascular hyperplasia by inhibiting phenotype modulation and proliferation through extracellular signal-regulated kinase 1 and 2 and p38 mitogen-activated protein kinase inactivation in organ-cultured artery.
abstract: OBJECTIVE
  We examined the inhibitory mechanisms of fluvastatin on FBS-induced vascular hypertrophy assessed by organ-cultured rat tail artery.
  
  
  RESULTS
  After 5 days of culture with 10% FBS, hyperplastic morphological changes in the media layer were induced. Treatment with 1 mumol/L fluvastatin significantly inhibited these changes. In the FBS-cultured arteries, the protein expression ratio of alpha-actin/beta-actin was significantly decreased, indicating the change to synthetic phenotype. Fluvastatin restored the decreased expression ratio, and the addition of mevalonate (100 mumol/L) suppressed this recovery. In accordance with the synthetic morphological changes, the absolute force of contractions induced by stimuli was decreased. Fluvastatin treatment also restored the decreased contractility, and the addition of mevalonate suppressed this recovery. In the arteries cultured with FBS, extracellular signal-regulated kinase 1 and 2 (ERK1/2) and p38 mitogen-activated protein kinase (p38MAPK) phosphorylation were significantly increased. Fluvastatin inhibited these phosphorylations, and mevalonate prevented the action of fluvastatin.
  
  
  CONCLUSIONS
  These results suggest that fluvastatin inhibits vascular smooth muscle phenotype modulation to synthetic phenotype and proliferation by inhibiting the local metabolic pathway of cholesterol in smooth muscle cells, which inhibits hyperplastic changes in the vascular wall. The antihyperplastic actions by statins may be induced by inhibiting the ERK1/2 and p38MAPK activities, possibly through inhibition of prenylated Ras. We examined the inhibitory mechanisms of fluvastatin on FBS-induced vascular hypertrophy assessed by organ-cultured artery. Results suggest that fluvastatin inhibits vascular smooth muscle phenotype modulation and proliferation by inhibiting the ERK1/2 and p38MAPK activities through depletion of mevalonate in smooth muscle cells, resulting in inhibiting vascular hyperplastic changes.
authors.affiliation: Department of Veterinary Pharmacology, Graduate School of Agriculture and Life Sciences, The University of Tokyo, Japan.
authors.forename: Kenichi
authors.initials: K
authors.lastname: Sakamoto
authors.forename: Takahisa
authors.initials: T
authors.lastname: Murata
authors.forename: Hiroko
authors.initials: H
authors.lastname: Chuma
authors.forename: Masatoshi
authors.initials: M
authors.lastname: Hori
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Ozaki
mesh_terms: D000818:Animals; D001158:Arteries; D002455:Cell Division / Q000187:drug effects; D002784:Cholesterol / Q000378:metabolism; D016895:Culture Media, Serum-Free; D005229:Fatty Acids, Monounsaturated / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D000077340:Fluvastatin; D006965:Hyperplasia; D007211:Indoles / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D008297:Male; D008798:Mevalonic Acid / Q000494:pharmacology; D019950:Mitogen-Activated Protein Kinase 1 / Q000037:antagonists & inhibitors*; D048052:Mitogen-Activated Protein Kinase 3 / Q000037:antagonists & inhibitors*; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000378:metabolism; D009924:Organ Culture Techniques; D010641:Phenotype; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D017368:Protein Prenylation / Q000187:drug effects; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D016283:Proto-Oncogene Proteins p21(ras) / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction / Q000187:drug effects; D013623:Tail / Q000098:blood supply; D014661:Vasoconstriction / Q000187:drug effects; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors*
chemical_list: D016895:Culture Media, Serum-Free; D005229:Fatty Acids, Monounsaturated; D007211:Indoles; D047428:Protein Kinase Inhibitors; D000077340:Fluvastatin; D002784:Cholesterol; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D048051:p38 Mitogen-Activated Protein Kinases; D016283:Proto-Oncogene Proteins p21(ras); D008798:Mevalonic Acid