@article{APS3848,
author = {Hung-hsing Chao and Ju-chi Liu and Jia-wei Lin and Cheng-hsien Chen and Chieh-hsi Wu and Tzu-humg Cheng},
title = {Uric acid stimulates endothelin-1 gene expression associated with NADPH oxidase in human aortic smooth muscle cells},
journal = {Acta Pharmacologica Sinica},
volume = {29},
number = {11},
year = {2016},
keywords = {},
abstract = {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 p47phox 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.},
issn = {1745-7254}, url = {http://www.chinaphar.com/article/view/3848}
}