on May 12, 2003
Hypertension. 2003
Published online before print May 12, 2003, doi: 10.1161/01.HYP.0000072820.07472.3B
Published online before print May 12, 2003, doi: 10.1161/01.HYP.0000072820.07472.3B
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Submitted on January 8, 2003
From Nephrology, Baylor College of Medicine (J.K., S.W., J.H.L., D.H.K., P.L., T.N., A.W., D.S., H.Y.L., L.F., R.J.J.), Houston, Tex; Department of Medicine, University of Melbourne, and Department of Nephrology, Austin and Repatriation Medical Centre (J.K.), Heidelberg, Victoria, Australia; and Division of Nephrology, Ewha Women's University (D.H.K.), Seoul, Korea. * To whom correspondence should be addressed. E-mail: rjohnson{at}bcm.tmc.edu.
Abstract--Previous studies have reported that uric acid stimulates vascular smooth muscle cell (VSMC) proliferation in vitro. We hypothesized that uric acid may also have direct proinflammatory effects on VSMCs. Crystal- and endotoxin-free uric acid was found to increase VSMC monocyte chemoattractant protein-1 (MCP-1) expression in a time- and dose-dependent manner, peaking at 24 hours. Increased mRNA and protein expression occurred as early as 3 hours after uric acid incubation and was partially dependent on posttranscriptional modification of MCP-1 mRNA. In addition, uric acid activated the transcription factors nuclear factor-
Revised on February 6, 2003
Uric Acid Stimulates Monocyte Chemoattractant Protein-1 Production in Vascular Smooth Muscle Cells Via Mitogen-Activated Protein Kinase and Cyclooxygenase-2
John Kanellis;
B and activator protein-1, as well as the MAPK signaling molecules ERK p44/42 and p38, and increased cyclooxygenase-2 (COX-2) mRNA expression. Inhibition of p38 (with SB 203580), ERK 44/42 (with UO126 or PD 98059), or COX-2 (with NS398) each significantly suppressed uric acid-induced MCP-1 expression at 24 hours, implicating these pathways in the response to uric acid. The ability of both N-acetyl-cysteine and diphenyleneionium (antioxidants) to inhibit uric acid-induced MCP-1 production suggested involvement of intracellular redox pathways. Uric acid regulates critical proinflammatory pathways in VSMCs, suggesting it may have a role in the vascular changes associated with hypertension and vascular disease.
Key words: atherosclerosis • chemokines • hyperuricemia • arteriolosclerosis
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