Endothelial nitric oxide synthase is a critical factor in experimental liver fibrosis

Int J Exp Pathol. 2008 Aug;89(4):241-50. doi: 10.1111/j.1365-2613.2008.00590.x. Epub 2008 Apr 21.


Reduced expression of endothelial nitric oxide synthase (eNOS) in chronic liver disease can reduce hepatic perfusion and accelerate fibrosis. The relationship between eNOS expression and liver fibrogenesis remains unclear. We investigated whether L-arginine attenuated chronic liver fibrosis through eNOS expression. Chronic liver injury was induced by administration of carbon tetrachloride (CCl(4)) to mice for 8 weeks. 5-Methylisothiourea hemisulphate (SMT), an iNOS inhibitor, or L-arginine, a NOS substrate were injected subcutaneously. CCl(4)-induced hepatotoxicity, oxidative stress and accumulation of collagen were detected in the liver. The expression levels of inducible NOS (iNOS) and nuclear factor kappa-B (NF-kappaB) activity in the liver after CCl(4) treatment were increased but eNOS expression and activator protein-1 (AP-1) activity were decreased. Both SMT and L-arginine effectively reduced CCl(4) induced oxidative stress and collagen formation, but L-arginine showed a significantly greater suppression of collagen formation, iNOS expression and NF-kappaB activity. L-arginine also restored the level of eNOS and AP-1 activity. L-arginine was more effective than SMT in suppressing liver fibrosis. L-arginine might improve NO production which facilitates hepatic blood flow and thus retards liver fibrogenesis. Our results showed that the reduced eNOS expression in CCl(4)-treated mice was reversed by L-arginine. Furthermore, L-arginine also reversed the reduced AP-1 activity, an eNOS promoter.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alanine Transaminase / metabolism
  • Animals
  • Arginine / pharmacology
  • Blotting, Western / methods
  • Carbon Tetrachloride
  • Chronic Disease
  • Disease Progression
  • Electrophoretic Mobility Shift Assay / methods
  • Isothiuronium / analogs & derivatives
  • Isothiuronium / pharmacology
  • Liver / chemistry
  • Liver / enzymology*
  • Liver Cirrhosis / enzymology*
  • Male
  • Mice
  • Mice, Inbred ICR
  • Models, Animal
  • NF-kappa B / analysis
  • Nitric Oxide Synthase Type II / analysis
  • Nitric Oxide Synthase Type II / antagonists & inhibitors
  • Nitric Oxide Synthase Type II / genetics
  • Nitric Oxide Synthase Type III / analysis
  • Nitric Oxide Synthase Type III / genetics
  • Nitric Oxide Synthase Type III / metabolism*
  • Oxidative Stress
  • Procollagen / genetics
  • RNA, Messenger / analysis
  • Reverse Transcriptase Polymerase Chain Reaction
  • Transcription Factor AP-1 / analysis
  • Transforming Growth Factor beta1 / genetics


  • NF-kappa B
  • Procollagen
  • RNA, Messenger
  • Transcription Factor AP-1
  • Transforming Growth Factor beta1
  • Isothiuronium
  • Arginine
  • Carbon Tetrachloride
  • Nitric Oxide Synthase Type II
  • Nitric Oxide Synthase Type III
  • Alanine Transaminase
  • S-methylisothiopseudouronium