Abstract 12851: Endothelial Dysfunction in Rheumatoid Arthritis: The Role of Monocyte Chemotactic Protein-1-Induced Protein
Background Patients with rheumatoid arthritis (RA) are prone to atherosclerosis. However, the molecular mechanism by which RA causes endothelial dysfunction leading to atherosclerosis is largely unknown. We explored the role of elevated level of monocyte chemotactic protein-1 (MCP-1)-induced protein (MCPIP) in endothelial dysfunction associated with RA.
Methods and Results The level of MCP-1 was elevated in sera from mice with collagen-induced arthritis (CIA), which negatively correlated with endothelium-dependent vessel dilation. Aortas from CIA mice showed increased expression of MCPIP but decreased endothelial nitric oxide synthase (eNOS)-derived nitric oxide (NO) bioavailability. Administrating CIA mice with MCP-1 neutralized antibody decreased the MCPIP in aortas with alleviated endothelial dysfunction. In vitro, treating cultured endothelial cells (ECs) with MCP-1 or sera from CIA mice or RA patients increased the expression of MCPIP whereas inhibited the Akt and eNOS phosphorylation. These detrimental effects were reproduced in ECs over-expressing MCPIP with elevated redox stress. Agonist against the MCP-1 receptor or siRNA knocking down MCPIP restored the eNOS-derived NO bioavailability. Importantly, administration of CIA mice with simvastatin ameliorated the endothelial dysfunction with attendant decreased MCPIP level in the aorta. At the molecular level, the beneficial effect of statin was mediated through an inhibition of NF-κB binding to the enhancer of the MCPIP gene.
Conclusions Our results suggest that the increased MCPIP plays an important role in RA leading to endothelial dysfunction. Statin treatment or MCP-1 neutralized antibody therapy may antagonize MCPIP, thereby attenuating endothelial dysfunction associated with RA.
- © 2012 by American Heart Association, Inc.