Melatonin blocks oxidative stress-induced increased asymmetric dimethylarginine

You Lin Tain, Ying Hsien Kao, Chih Sung Hsieh, Chih Cheng Chen, Jiunn Ming Sheen, I. Chun Lin, Li Tung Huang*

*Corresponding author for this work

Research output: Contribution to journalJournal Article peer-review

62 Scopus citations

Abstract

Asymmetric dimethylarginine (ADMA) is a competitive inhibitor of nitric oxide synthase, and its increase is associated with many systemic diseases. We recently found that increases in plasma and hepatic ADMA levels were associated with oxidative stress in young bile-duct-ligation (BDL) rats; these increases were prevented by melatonin therapy. Therefore, we used an in vivo BDL model and in vitro cultured hepatocytes to elucidate the protective mechanisms of melatonin against oxidative stress-induced increase in ADMA. We found that the presence of reactive oxygen species (ROS) in young rats with BDL leads to downregulation of dimethylarginine dimethyaminohydrolase (DDAH)-1 and -2 as well as DDAH activity. Melatonin prevented ADMA increases in the liver mainly by regulating DDAH-1 and -2. The expression and activity of DDAH were suppressed in vitro by superoxide and hydrogen peroxide (H2O2) in a time-dependent manner, whereas melatonin could block H2O2-induced downregulation of DDAH-2 as well as decreased DDAH activity, thereby preventing increases in hepatic ADMA. Our findings reveal a mechanistic basis of DDAH downregulation by ROS and suggest that melatonin might be a potential therapy for various diseases with elevated cellular ADMA.

Original languageEnglish
Pages (from-to)1088-1098
Number of pages11
JournalFree Radical Biology and Medicine
Volume49
Issue number6
DOIs
StatePublished - 09 2010
Externally publishedYes

Keywords

  • Asymmetric dimethylarginine
  • Free radicals
  • Melatonin
  • Nitric oxide
  • Oxidative stress

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