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

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 acidinduced 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 apocynin (1-[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.

Molecular Mechanisms Underlying Urate-Induced Enhancement of Kv1.5 Channel Expression in HL-1 Atrial Myocytes

“…10,12,15 Urate stimulates the production of oxidant in both adipocytes and vascular smooth muscle cells. 17, 41 We observed an increase of ROS in urate-treated HL-1 cells. This increase was proportional to the increase of Kv1.5 proteins.…”

“…Chao et al reported that urate stimulated the expression of endothelin-1 and NADPH oxidase in human aortic smooth muscle cells. 41 Taken together, we conclude that urate-induced oxidative stress via activation of NADPH oxidase increased the protein level of Kv1.5.…”

“…ROS is well-known to be generated by NADPH oxidase and urate-induced ROS production via activation of NADPH oxidase. 41 The NADPH oxidase inhibitor, apocynin, reduced the ROS level and inhibited the urate-induced enhancement of Kv1.5 expression. Chao et al reported that urate stimulated the expression of endothelin-1 and NADPH oxidase in human aortic smooth muscle cells.…”

Uric Acid as a Potential Biomarker of Pulmonary Arterial Hypertension in Patients with Sickle Cell Disease

“…Several recent studies have shown that the UA might contribute in the pathophysiology of PAH. For example, UA increases cyclo-oxygenase-2 and ET-1 expression in vascular smooth muscle cells (VSMC) [18,19]. UA also inhibits vasodilatation in the lung by reducing nitric oxide production by endothelial cells [20].…”

Comparing the Effects of Inorganic Nitrate and Allopurinol in Renovascular Complications of Metabolic Syndrome in Rats: Role of Nitric Oxide and Uric Acid

“…On the other hand, uric acid loses its antioxidant ability in the hydrophobic environment [10]. It was shown that soluble uric acid -alone or combined with peroxy nitrite -stimulates an increase in nicotinamide adenine dinucleotide phosphate (NADPH) oxidase acti vi ty and increases production of reactive oxygen species in mature adipocytes, which result in increased protein nitrosylation and lipid oxidation [11,12].…”