α-Lipoic acid activates dimethylarginine dimethylaminohydrolase in cultured endothelial cells

Asymmetric dimethylarginine (ADMA) is a risk factor of cardiovascular diseases. α-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.

Research highlights
► α-Lipoic acid (ALA) decreases ADMA level in culture media of endothelial cells.
► ALA increases the gene expression and activity of DDAH in endothelial cells.
► ALA regulates endothelial function by modulating DDAH activity and gene expression.