PMID- 22396501
OWN - NLM
STAT- MEDLINE
DCOM- 20121123
LR  - 20181201
IS  - 1755-3245 (Electronic)
IS  - 0008-6363 (Linking)
VI  - 95
IP  - 2
DP  - 2012 Jul 15
TI  - Statin inhibits hypoxia-induced endothelin-1 via accelerated degradation of 
      HIF-1alpha in vascular smooth muscle cells.
PG  - 251-9
LID - 10.1093/cvr/cvs110 [doi]
AB  - AIMS: 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). METHODS AND 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 micromol/L or greater, fluvastatin attenuated the hypoxia-induced ET-1 gene 
      expression through the accelerated ubiquitin/proteasome-dependent degradation of 
      HIF-1alpha, thus consequently attenuating HIF-1alpha 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. CONCLUSION: The present study suggests that fluvastatin attenuates 
      HIF-1-dependent ET-1 gene expression in conjunction with the stimulation of 
      HIF-1alpha ubiquitin/proteasome-dependent degradation via isoprenoid-dependent 
      mechanisms.
FAU - Hisada, Tetsuya
AU  - Hisada T
AD  - Department of Preventive Medicine and Public Health, National Defense Medical 
      College, 3-2 Namiki, Tokorozawa, Saitama 359-8513, Japan. hisadat@ndmc.ac.jp
FAU - Ayaori, Makoto
AU  - Ayaori M
FAU - Ohrui, Nobuhiro
AU  - Ohrui N
FAU - Nakashima, Hiroshi
AU  - Nakashima H
FAU - Nakaya, Kazuhiro
AU  - Nakaya K
FAU - Uto-Kondo, Harumi
AU  - Uto-Kondo H
FAU - Yakushiji, Emi
AU  - Yakushiji E
FAU - Takiguchi, Shunichi
AU  - Takiguchi S
FAU - Terao, Yoshio
AU  - Terao Y
FAU - Miyamoto, Yoshinori
AU  - Miyamoto Y
FAU - Adachi, Takeshi
AU  - Adachi T
FAU - Nakamura, Haruo
AU  - Nakamura H
FAU - Ohsuzu, Fumitaka
AU  - Ohsuzu F
FAU - Ikewaki, Katsunori
AU  - Ikewaki K
FAU - Sakurai, Yutaka
AU  - Sakurai Y
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20120306
PL  - England
TA  - Cardiovasc Res
JT  - Cardiovascular research
JID - 0077427
RN  - 0 (Endothelin-1)
RN  - 0 (Fatty Acids, Monounsaturated)
RN  - 0 (Hydroxymethylglutaryl-CoA Reductase Inhibitors)
RN  - 0 (Hypoxia-Inducible Factor 1, alpha Subunit)
RN  - 0 (Indoles)
RN  - 0 (Transcription Factors)
RN  - 4L066368AS (Fluvastatin)
SB  - IM
MH  - Cells, Cultured
MH  - Endothelin-1/*metabolism
MH  - Fatty Acids, Monounsaturated/*pharmacology
MH  - Fluvastatin
MH  - Humans
MH  - Hydroxymethylglutaryl-CoA Reductase Inhibitors/*pharmacology
MH  - Hypoxia/metabolism
MH  - Hypoxia-Inducible Factor 1, alpha Subunit/genetics/*metabolism
MH  - Indoles/*pharmacology
MH  - Myocytes, Smooth Muscle/*metabolism
MH  - Proteolysis/drug effects
MH  - Transcription Factors
EDAT- 2012/03/08 06:00
MHDA- 2012/12/10 06:00
CRDT- 2012/03/08 06:00
PHST- 2012/03/08 06:00 [entrez]
PHST- 2012/03/08 06:00 [pubmed]
PHST- 2012/12/10 06:00 [medline]
AID - cvs110 [pii]
AID - 10.1093/cvr/cvs110 [doi]
PST - ppublish
SO  - Cardiovasc Res. 2012 Jul 15;95(2):251-9. doi: 10.1093/cvr/cvs110. Epub 2012 Mar 
      6.