Endothelial dysfunction in rheumatoid arthritis: the role of monocyte chemotactic protein-1-induced protein.
OBJECTIVE
Patients with rheumatoid arthritis are prone to atherosclerosis. We explored the role of elevated level of monocyte chemotactic protein-1 (MCP-1)-induced protein (MCPIP) in endothelial dysfunction associated with rheumatoid arthritis.


APPROACH AND RESULTS
The level of MCP-1 was elevated in sera from mice with collagen-induced arthritis (CIA) and was negatively correlated with endothelium-dependent vessel dilation. Aortas from CIA mice showed increased expression of MCPIP but decreased bioavailability of endothelial NO synthase-derived NO. Administering MCP-1 neutralizing antibody to CIA mice decreased the MCPIP level in aortas and alleviated endothelial dysfunction. In vitro, treating cultured vascular endothelial cells with MCP-1 or sera from CIA mice or rheumatoid arthritis patients increased the expression of MCPIP but inhibited endothelial NO synthase phosphorylation. These detrimental effects were reproduced in endothelial cells overexpressing MCPIP, with elevated redox stress. Small interfering RNA knockdown of MCPIP restored the endothelial NO synthase-derived NO bioavailability. Administering simvastatin to CIA mice ameliorated the endothelial dysfunction, with attendant decreased aortic level of MCPIP. The beneficial effect of the statin was mediated by inhibiting nuclear factor κB binding to the MCPIP gene enhancer.


CONCLUSIONS
Increased MCPIP is found in rheumatoid arthritis leading to endothelial dysfunction. Statin treatment or MCP-1 neutralizing antibody administration antagonizes MCPIP expression, thereby attenuating the endothelial dysfunction.
['He|Ming|M|', 'Liang|Xiao|X|', 'He|Lan|L|', 'Wen|Wen|W|', 'Zhao|Sijia|S|', 'Wen|Liang|L|', 'Liu|Yan|Y|', 'Shyy|John Y-J|JY|', 'Yuan|Zuyi|Z|']
D000818:Animals D001169:Arthritis, Experimental D001172:Arthritis, Rheumatoid D050197:Atherosclerosis D015415:Biomarkers D002478:Cells, Cultured D018932:Chemokine CCL2 D004195:Disease Models, Animal D015536:Down-Regulation D042783:Endothelial Cells D005786:Gene Expression Regulation D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors D051379:Mice D008815:Mice, Inbred Strains D019001:Nitric Oxide Synthase D011897:Random Allocation D012044:Regression Analysis D012260:Ribonucleases
endothelial dysfunction rheumatoid arthritis atherosclerosis monocyte chemotactic protein-1–induced protein