Uric Acid Stimulates Monocyte Chemoattractant Protein-1 Production in Vascular Smooth Muscle Cells Via Mitogen-Activated Protein Kinase and Cyclooxygenase-2

Abstract

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-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.

Absence of an independent association between serum uric acid and left ventricular mass in Caucasian hypertensive women and men

“…Previous reports have shown that uric acid induces endothelial dysfunction and smooth muscle cell proliferation by activating the RAS and inflammatory mediators such as tumor necrosis factor-alpha and mitogen-activated protein kinases, which are known to induce cardiac hypertrophy [1,10,11,30]. It has been also reported that uric acid in vitro may increase endothelin-1 gene expression in rat cardiac fibroblasts [12].…”

Uric acid and the cardiovascular profile of African and Caucasian men

“…30 There are multiple ways in which UA can most likely cause vascular remodelling. UA can alter the proliferation and migration of vascular smooth muscle cells 31,32 by activating a series of pathways including mitogen-activated protein kinases, 32,33 platelet-derived growth factors, chemokines (monocyte chemoattractant protein-1), and inflammatory enzymes (COX-2). 32,33 Besides its possible direct effect on vascular smooth muscle cells proliferation and migration, UA may also exert other detrimental effects on the vascular system.…”

“…UA can alter the proliferation and migration of vascular smooth muscle cells 31,32 by activating a series of pathways including mitogen-activated protein kinases, 32,33 platelet-derived growth factors, chemokines (monocyte chemoattractant protein-1), and inflammatory enzymes (COX-2). 32,33 Besides its possible direct effect on vascular smooth muscle cells proliferation and migration, UA may also exert other detrimental effects on the vascular system. It is speculated that UA alters the release of endothelial nitric oxide, 34,35 allowing the endothelium to convert from a vasoprotective environment to one that is vasoconstrictive, procoagulant and antifibrinolytic.…”

The diverse associations of uric acid with low-grade inflammation, adiponectin and arterial stiffness in never-treated hypertensives

“…[2][3][4][5] Several pathophysiological mechanisms linking SUA to adverse cardiovascular outcome have been proposed, including proliferation of vascular smooth muscle cells, 6 prothrombotic effects mediated by platelet activation, 7 impaired nitric oxide generation and endothelial dysfunction, 8 activation of local renin-angiotensin-aldosterone system 9 and stimulation of inflammatory pathways. 10 Inflammation seems to have a pivotal role in the pathogenesis of hypertension and hypertensive target organ damage. In these lines, we have recently shown that high-sensitivity CRP (hs-CRP) is associated with microalbuminuria, 11 whereas increased hs-CRP and decreased adiponectin levels go together with a state of increased aortic stiffness in hypertensives.…”