Dihydromyricetin Attenuates TNF- α-Induced Endothelial Dysfunction through miR-21-Mediated DDAH1/ADMA/NO Signal Pathway

Biomed Res Int. 2018 Feb 28;2018:1047810. doi: 10.1155/2018/1047810. eCollection 2018.


Accumulating studies demonstrate that dihydromyricetin (DMY), a compound extracted from Chinese traditional herb, Ampelopsis grossedentata, attenuates atherosclerotic process by improvement of endothelial dysfunction. However, the underlying mechanism remains poorly understood. Thus, the aim of this study is to investigate the potential mechanism behind the attenuating effects of DMY on tumor necrosis factor alpha- (TNF-α-) induced endothelial dysfunction. In response to TNF-α, microRNA-21 (miR-21) expression was significantly increased in human umbilical vein endothelial cells (HUVECs), in line with impaired endothelial dysfunction as evidenced by decreased tube formation and migration, endothelial nitric oxide synthase (eNOS) (ser1177) phosphorylation, dimethylarginine dimethylaminohydrolases 1 (DDAH1) expression and metabolic activity, and nitric oxide (NO) concentration as well as increased asymmetric dimethylarginine (ADMA) levels. In contrast, DMY or blockade of miR-21 expression ameliorated endothelial dysfunction in HUVECs treated with TNF-α through downregulation of miR-21 expression, whereas these effects were abolished by overexpression of miR-21. In addition, using a nonspecific NOS inhibitor, L-NAME, also abrogated the attenuating effects of DMY on endothelial dysfunction. Taken together, these data demonstrated that miR-21-mediated DDAH1/ADMA/NO signal pathway plays an important role in TNF-α-induced endothelial dysfunction, and DMY attenuated endothelial dysfunction induced by TNF-α in a miR-21-dependent manner.

MeSH terms

  • Amidohydrolases / metabolism*
  • Arginine / analogs & derivatives*
  • Arginine / metabolism
  • Cells, Cultured
  • Down-Regulation / drug effects
  • Flavonols / pharmacology*
  • Human Umbilical Vein Endothelial Cells / drug effects*
  • Human Umbilical Vein Endothelial Cells / metabolism
  • Humans
  • MicroRNAs / metabolism*
  • Nitric Oxide / metabolism*
  • Nitric Oxide Synthase Type III / metabolism
  • Signal Transduction / drug effects
  • Tumor Necrosis Factor-alpha / metabolism*


  • Flavonols
  • MIRN21 microRNA, human
  • MicroRNAs
  • Tumor Necrosis Factor-alpha
  • Nitric Oxide
  • N,N-dimethylarginine
  • Arginine
  • Nitric Oxide Synthase Type III
  • Amidohydrolases
  • dimethylargininase
  • dihydromyricetin