Published online before print May 12, 2003, doi: 10.1161/01.HYP.0000072820.07472.3B
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(Hypertension. 2003;41:1287.)
© 2003 American Heart Association, Inc.
Scientific Contributions |
Uric Acid Stimulates Monocyte Chemoattractant Protein-1 Production in Vascular Smooth Muscle Cells Via Mitogen-Activated Protein Kinase and Cyclooxygenase-2
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.
Correspondence to Richard J Johnson MD, Division of Nephrology, Baylor College of Medicine, SM-1273, 6550 Fannin St, Houston TX 77030. E-mail rjohnson{at}bcm.tmc.edu
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-
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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