title: Statin protects endothelial nitric oxide synthase activity in hypoxia-induced pulmonary hypertension.
abstract: OBJECTIVE
  We investigated the effects of fluvastatin on hypoxia-induced (1 to 3 weeks, 10% O2) pulmonary hypertension with focus on endothelial nitric oxide synthase (eNOS) activity.
  
  
  RESULTS
  Oral fluvastatin treatment (1 mg/kg daily) prevented the causing and progression of pulmonary hypertension as determined by the right ventricular pressure, right ventricular hypertrophy, and muscularization of pulmonary artery. We also revealed that fluvastatin treatments prevented the hypoxia-induced decrease in cGMP production in the rat lung and restored the endothelium-dependent relaxation in the pulmonary artery. We revealed that this beneficial effect was not dependent on the increase in eNOS mRNA or protein expression, but was dependent on the inhibition of the eNOS-tight coupling with caveolin-1, the eNOS dissociation from heat shock protein 90, and the decrease in eNOS Ser1177-phosphorylation induced by hypoxia. Furthermore, in a whole-mount immunostaining the hypoxia-induced eNOS protein condensation with caveolin-1 of pulmonary endothelial cells was restored by the fluvastatin-treatment.
  
  
  CONCLUSIONS
  These results suggest that the fluvastatin exerts beneficial effects on chronic hypoxia-induced pulmonary hypertension by protecting against the eNOS activity at the post-transcriptional level.
authors.affiliation: Department of Veterinary Pharmacology, Graduate School of Agriculture and Life Sciences, The University of Tokyo, Tokyo 113-8657, Japan. murata@mail.vm.a.u-tokyo.ac.jp
authors.forename: Takahisa
authors.initials: T
authors.lastname: Murata
authors.forename: Kazuya
authors.initials: K
authors.lastname: Kinoshita
authors.forename: Masatoshi
authors.initials: M
authors.lastname: Hori
authors.forename: Masayoshi
authors.initials: M
authors.lastname: Kuwahara
authors.forename: Hirokazu
authors.initials: H
authors.lastname: Tsubone
authors.forename: Hideaki
authors.initials: H
authors.lastname: Karaki
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Ozaki
mesh_terms: D000818:Animals; D001794:Blood Pressure; D051242:Caveolin 1 / Q000378:metabolism; D002908:Chronic Disease; D006152:Cyclic GMP / Q000378:metabolism; D004562:Electrocardiography; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000201:enzymology; D005229:Fatty Acids, Monounsaturated / Q000494:pharmacology*; D000077340:Fluvastatin; D018841:HSP90 Heat-Shock Proteins / Q000378:metabolism; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D006976:Hypertension, Pulmonary / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism*; D000860:Hypoxia / Q000150:complications / Q000378:metabolism; D007211:Indoles / Q000494:pharmacology*; D009206:Myocardium / Q000473:pathology; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism*; D009929:Organ Size; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011651:Pulmonary Artery / Q000378:metabolism / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D014664:Vasodilation / Q000187:drug effects / Q000502:physiology; D016278:Ventricular Function, Right
chemical_list: D051242:Caveolin 1; D005229:Fatty Acids, Monounsaturated; D018841:HSP90 Heat-Shock Proteins; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007211:Indoles; D000077340:Fluvastatin; D052250:Nitric Oxide Synthase Type III; D051057:Proto-Oncogene Proteins c-akt; D006152:Cyclic GMP