Statin inhibits hypoxia-induced endothelin-1 via accelerated degradation of HIF-1α in vascular smooth muscle cells Full Text
Cardiovascular Research, 07/17/2012
Hisada T et al. – 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.Methods
- Hypoxia (1% O2), compared with the normoxic condition (21% O2), 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.