Uric acid stimulates endothelin-1 gene expression associated with NADPH oxidase in human aortic smooth muscle cells

Hung Hsing Chao, Ju Chi Liu, Jia Wei Lin, Cheng Hsien Chen, Chieh Hsi Wu, Tzu Humg Cheng

Research output: Contribution to journalArticlepeer-review

63 Citations (Scopus)


Aim: Recent experimental and human studies have shown that hyperuricemia is associated with hypertension and cardiovascular diseases. Elevated levels of endothelin-1 (ET-1) has been regarded as one of the most powerful independent predictors of cardiovascular diseases. For investigating whether uric acid-induced vascular diseases are related to ET-1, the uric acid-induced ET-1 expression in human aortic smooth muscle cells (HASMC) was examined. Methods: Cultured HASMC treated with uric acid, cell proliferation and ET-1 expression were examined. Antioxidant pretreatments on uric acid-induced extracellular signal-regulated kinases (ERK) phosphorylation were carried out to elucidate the redox-sensitive pathway in proliferation and ET-1 gene expression. Results: Uric acid was found to increase HASMC proliferation, ET-1 expression and reactive oxygen species production. The ability of both N-acetylcysteine and apo-cynin (l-[4-hydroxy-3-methoxyphenyl]ethanone, a NADPH oxidase inhibitor) to inhibit uric acid-induced ET-1 secretion and cell proliferation suggested the involvement of intracellular redox pathways. Furthermore, apocynin, and p47 phox small interfering RNA knockdown inhibited ET-1 secretion and cell proliferation induced by uric acid. Inhibition of ERK by U0126 (1,4-diamino-2,3-dicyano-1,4-bis[2-aminophenylthio]butadiene) significantly suppressed uric acid-induced ET-1 expression, implicating this pathway in the response to uric acid. In addition, uric acid increased the transcription factor activator protein-1 (AP-1) mediated reporter activity, as well as the ERK phosphorylation. Mutational analysis of the ET-1 gene promoter showed that the AP-1 binding site was an important cis-element in uric acid-induced ET-1 gene expression. Conclusion: This is the first observation of ET-1 regulation by uric acid in HASMC, which implicates the important role of uric acid in the vascular changes associated with hypertension and vascular diseases.

Original languageEnglish
Pages (from-to)1301-1312
Number of pages12
JournalActa Pharmacologica Sinica
Issue number11
Publication statusPublished - Nov 2008
Externally publishedYes


  • Endothelin-1
  • Extracellular signal-regulated kinases
  • Human aortic smooth muscle cells
  • NADPH oxidase
  • Reactive oxygen species
  • Uric acid

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)


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