title: Statin inhibits hypoxia-induced endothelin-1 via accelerated degradation of HIF-1α in vascular smooth muscle cells.
abstract: OBJECTIVE
  Endothelin-1 (ET-1) contributes to the pathogenesis of cardiovascular diseases with multiple properties such as vasoconstriction. Human ET-1 gene expression is up-regulated by the transcription factor hypoxia-inducible factor-1 (HIF-1) through hypoxia response element (HRE). Although previous studies suggested that 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) alter HIF-1-related gene expression, it remained unclear whether statins modulate HIF-1-mediated ET-1 expression. Therefore, we investigated the effect of fluvastatin on hypoxia-induced human ET-1 expression in vascular smooth muscle cells (VSMC).
  
  
  RESULTS
  Hypoxia (1% O(2)), compared with the normoxic condition (21% O(2)), significantly induced the expression of preproET-1 mRNA, ET-1 protein, and ET-1 secretion in VSMC. Hypoxia induced a 2.3-fold increase in HRE-dependent ET-1 reporter gene activation. Under concentrations of 1 µmol/L or greater, fluvastatin attenuated the hypoxia-induced ET-1 gene expression through the accelerated ubiquitin/proteasome-dependent degradation of HIF-1α, thus consequently attenuating HIF-1α binding to the HRE of the ET-1 gene. These inhibitory effects of fluvastatin were cancelled by concomitant treatment with mevalonate, farnesyl pyrophosphate, or geranylgeranyl pyrophosphate, but not squalene.
  
  
  CONCLUSIONS
  The present study suggests that fluvastatin attenuates HIF-1-dependent ET-1 gene expression in conjunction with the stimulation of HIF-1α ubiquitin/proteasome-dependent degradation via isoprenoid-dependent mechanisms.
authors.affiliation: Department of Preventive Medicine and Public Health, National Defense Medical College, 3-2 Namiki, Tokorozawa, Saitama 359-8513, Japan. hisadat@ndmc.ac.jp
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Hisada
authors.forename: Makoto
authors.initials: M
authors.lastname: Ayaori
authors.forename: Nobuhiro
authors.initials: N
authors.lastname: Ohrui
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Nakashima
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Nakaya
authors.forename: Harumi
authors.initials: H
authors.lastname: Uto-Kondo
authors.forename: Emi
authors.initials: E
authors.lastname: Yakushiji
authors.forename: Shunichi
authors.initials: S
authors.lastname: Takiguchi
authors.forename: Yoshio
authors.initials: Y
authors.lastname: Terao
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Miyamoto
authors.forename: Takeshi
authors.initials: T
authors.lastname: Adachi
authors.forename: Haruo
authors.initials: H
authors.lastname: Nakamura
authors.forename: Fumitaka
authors.initials: F
authors.lastname: Ohsuzu
authors.forename: Katsunori
authors.initials: K
authors.lastname: Ikewaki
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Sakurai
mesh_terms: D002478:Cells, Cultured; D019332:Endothelin-1 / Q000378:metabolism*; D005229:Fatty Acids, Monounsaturated / Q000494:pharmacology*; D000077340:Fluvastatin; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D000860:Hypoxia / Q000378:metabolism; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism*; D007211:Indoles / Q000494:pharmacology*; D032389:Myocytes, Smooth Muscle / Q000378:metabolism*; D059748:Proteolysis / Q000187:drug effects; D014157:Transcription Factors
chemical_list: D019332:Endothelin-1; D005229:Fatty Acids, Monounsaturated; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007211:Indoles; D014157:Transcription Factors; D000077340:Fluvastatin