Alpha-lipoic acid activates dimethylarginine dimethylaminohydrolase in cultured endothelial cells.
Asymmetric dimethylarginine (ADMA) is a risk factor of cardiovascular diseases. alpha-Lipoic acid (ALA) was shown to improve vascular dysfunction, and to decrease plasma ADMA level. In this study, we investigated whether ALA activates dimethylarginine dimethylaminohydrolase (DDAH), the metabolizing enzyme of ADMA, in cultured endothelial cells. ALA significantly decreased ADMA level in culture media of endothelial cells. ALA increased the gene expression and activity of DDAH, and signal transducer and activator of transcription (STAT)3 phosphorylation. Transfection of STAT3 increased DDAH II promoter activity, and ALA amplified it. ALA-induced increase in DDAH II promoter activity was attenuated in the promoter that had mutation in putative STAT3-binding site. These results suggest that ALA reduces ADMA level by enhancing DDAH activity and DDAH II gene expression, thus providing a novel mechanism by which ALA regulates endothelial function.
Lee
Woo Je
WJ
Department of Internal Medicine, University of Ulsan College of Medicine, Seoul, Republic of Korea.
Kim
Seung-Whan
SW
Kim
Seung-Hwan
SH
Kim
Geun Hyang
GH
Han
Sung Min
SM
Won
Jong Chul
JC
Jung
Chang Hee
CH
Park
Hye-Sun
HS
Choi
Do Sook
DS
Lee
Ki-Up
KU
Park
Joong-Yeol
JY
D000581:Amidohydrolases / Q000235:genetics*; D000818:Animals; D001120:Arginine / Q000031:analogs & derivatives* / Q000378:metabolism; D045744:Cell Line, Tumor; D042783:Endothelial Cells / Q000187:drug effects / Q000201:enzymology*; D004790:Enzyme Induction; D051379:Mice; D011401:Promoter Regions, Genetic; D050796:STAT3 Transcription Factor / Q000378:metabolism; D008063:Thioctic Acid / Q000494:pharmacology / Q000502:physiology*
D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; C018524:N,N-dimethylarginine; D008063:Thioctic Acid; D001120:Arginine; D000581:Amidohydrolases; C059999:dimethylargininase