Melatonin blocks oxidative stress-induced increased asymmetric dimethylarginine.
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 (H(2)O(2)) in a time-dependent manner, whereas melatonin could block H(2)O(2)-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.
Tain
You-Lin
YL
Department of Pediatrics, Chang Gung Memorial Hospital-Kaohsiung Medical Center, Chang Gung University College of Medicine, Kaohsiung 833, Taiwan.
Kao
Ying-Hsien
YH
Hsieh
Chih-Sung
CS
Chen
Chih-Cheng
CC
Sheen
Jiunn-Ming
JM
Lin
I-Chun
IC
Huang
Li-Tung
LT
D000581:Amidohydrolases / Q000235:genetics / Q000378:metabolism; D000818:Animals; D000831:Animals, Newborn; D001120:Arginine / Q000031:analogs & derivatives* / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D003135:Common Bile Duct / Q000187:drug effects / Q000601:surgery*; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D007274:Injections, Intraperitoneal; D008297:Male; D008550:Melatonin / Q000008:administration & dosage* / Q000494:pharmacology; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D018384:Oxidative Stress; D051381:Rats; D017207:Rats, Sprague-Dawley
C487735:dimethylarginine; D001120:Arginine; D019001:Nitric Oxide Synthase; D000581:Amidohydrolases; C059999:dimethylargininase; D008550:Melatonin