Download uric acid stimulates vascular smooth muscle cell proliferation by

1199, Either, cat: 25
URIC ACID STIMULATES VASCULAR SMOOTH MUSCLE CELL
PROLIFERATION BY INCREASING ENDOTHELIN-1 EXPRESSION
T.H. Cheng1,2 , H.H. Chao2,3, J.C. Liu1,2, H.Y. Yang1, J.Y. Liou3, K.G. Shyu2,3
1
Department of Medicine and Clinical Research Center, Taipei Medical University-Wan
Fang Hospital, Taipei, Taiwan, R.O.C, 2Graduate Institute of Medical Sciences, Taipei
Medical University, Taipei, Taiwan, R.O.C., 3Shin Kong Wu Ho-Su Memorial Hospital,
Taipei, Taiwan, R.O.C.
Literatures indicate that uric acid stimulates vascular smooth muscle cell (VSMC)
proliferation in vitro. However, the related intracellular mechanisms of uric acids in
VSMCs remain to be determined. Cultured rat aortic SMCs were stimulated with uric
acid, [3H]thymidine incorporation and the endothelin-1 (ET-1) gene expression was
examined. Antioxidants pretreatment on uric acid-induced extracellular signal-regulated
kinase (ERK) phosphorylation were performed to elucidate the redox-sensitive pathway
in proliferation and ET-1 gene expression. Crystal- and endotoxin-free uric acid increased
DNA synthesis which was inhibited with ETA receptor antagonist (BQ485). Uric acid
was found to increase VSMC ET-1 expression in a time- and dose-dependent manner.
Co-transfection of dominant negative mutant of Ras, Raf and MEK1 attenuated the uric
acid-increased ET-1 promoter activity, suggesting that the Ras-Raf-ERK pathway is
required for uric acid-induced ET-1 gene. Truncation and mutational analysis of the ET-1
gene promoter showed that activator protein-1 (AP-1) binding site was an important ciselement in uric acid-induced ET-1 gene expression. In addition, uric acid activated the
transcription factor AP-1, as well as the phosphorylation of ERK. Inhibition of ERK
(with UO126 or PD 98059) significantly suppressed uric acid-induced ET-1 expression at
24 hours, implicating these pathways in the response to uric acid. The ability of both Nacetylcysteine and diphenyleneionium (antioxidants) to inhibit uric acid¡Vinduced ET-1
production suggested involvement of intracellular redox pathways. Uric acid regulates
ET-1 in VSMCs, suggesting it may have a role in the vascular changes associated with
hypertension and vascular disease.