Angiotensin II type 1 receptor blockers prevent tumor necrosis factor-alpha-mediated endothelial nitric oxide synthase reduction and superoxide production in human umbilical vein endothelial cells

Eur J Pharmacol. 2010 Jun 25;636(1-3):36-41. doi: 10.1016/j.ejphar.2010.03.025. Epub 2010 Mar 29.


Decrease in endothelial nitric oxide synthase (eNOS) expression is one of the adverse outcomes of endothelial dysfunction. Tumor necrosis factor-alpha (TNF-alpha) is known to decrease eNOS expression and is an important mediator of endothelial dysfunction. We hypothesized that an angiotensin II type 1 (AT1) receptor blocker would improve endothelial function via not only inhibition of the angiotensin II signaling but also inhibition of the TNF-alpha-mediated signaling. Therefore we investigated whether an AT1 receptor blocker would restore the TNF-alpha-induced decrease in eNOS expression in cultured human umbilical vein endothelial cells (HUVEC). Pretreatment of HUVEC with an antioxidant (superoxide dismutase, alpha-tocopherol) or AT1 receptor blockers (olmesartan or candesartan) restored the TNF-alpha-dependent reduction of eNOS. The AT1 receptor blocker decreased the TNF-alpha-dependent increase of 8-isoprostane. The superoxide dismutase activities in HUVEC were stable during AT1 receptor blocker treatment, and the AT1 receptor blocker did not scavenge superoxide directly. The AT1 receptor blocker also decreased TNF-alpha-induced phosphorylation of I kappaB alpha and cell death. These results suggest that AT1 receptor blockers are able to ameliorate TNF-alpha-dependent eNOS reduction or cell injury by inhibiting superoxide production or nuclear factor-kappaB activation.

MeSH terms

  • Angiotensin II Type 1 Receptor Blockers / pharmacology*
  • Cell Death / drug effects
  • Cell Line, Tumor
  • Endothelial Cells / cytology
  • Endothelial Cells / drug effects*
  • Endothelial Cells / enzymology
  • Endothelial Cells / metabolism*
  • Free Radical Scavengers / pharmacology
  • Gene Expression Regulation, Enzymologic / drug effects
  • Humans
  • I-kappa B Proteins / metabolism
  • NF-KappaB Inhibitor alpha
  • Nitric Oxide Synthase Type III / metabolism*
  • Oxidative Stress / drug effects
  • Phosphorylation / drug effects
  • Superoxides / metabolism*
  • Tumor Necrosis Factor-alpha / metabolism*
  • Umbilical Veins / cytology*


  • Angiotensin II Type 1 Receptor Blockers
  • Free Radical Scavengers
  • I-kappa B Proteins
  • NFKBIA protein, human
  • Tumor Necrosis Factor-alpha
  • Superoxides
  • NF-KappaB Inhibitor alpha
  • Nitric Oxide Synthase Type III