Endothelial Dysfunction in Rheumatoid Arthritis The Role of Monocyte Chemotactic Protein-1-Induced Protein
Endothelial Dysfunction in Rheumatoid Arthritis The Role of Monocyte Chemotactic Protein-1-Induced Protein
复制标题
类风湿性关节炎的内皮功能障碍单核细胞趋化蛋白 1 诱导蛋白的作用
DOI：
10.1161/atvbaha.113.301490
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发表时间：
2013-06-01
影响因子：
8.7
通讯作者：
Yuan, Zuyi
中科院分区：
文献类型：
--
作者：
He, Ming;Liang, Xiao;Yuan, Zuyi
目的——类风湿性关节炎患者容易发生动脉粥样硬化。我们探讨了单核细胞趋化蛋白 1 (MCP-1) 诱导蛋白 (MCPIP) 水平升高在与类风湿性关节炎相关的内皮功能障碍中的作用。方法和结果——胶原诱导性关节炎 (CIA) 小鼠血清中 MCP-1 水平升高，且与内皮依赖性血管扩张呈负相关。 CIA 小鼠的主动脉显示 MCPIP 表达增加，但内皮 NO 合成酶衍生的 NO 的生物利用度降低。给 CIA 小鼠施用 MCP-1 中和抗体可降低主动脉中的 MCPIP 水平并减轻内皮功能障碍。在体外，用 MCP-1 或来自 CIA 小鼠或类风湿关节炎患者的血清处理培养的血管内皮细胞，可增加 MCPIP 的表达，但抑制内皮 NO 合酶磷酸化。这些有害影响在过度表达 MCPIP 的内皮细胞中重现，氧化还原应激升高。 MCPIP 的小干扰 RNA 敲除恢复了内皮 NO 合酶衍生的 NO 生物利用度。对 CIA 小鼠施用辛伐他汀可改善内皮功能障碍，同时降低主动脉 MCPIP 水平。他汀类药物的有益作用是通过抑制核因子κB与MCPIP基因增强子的结合来介导的。结论-在类风湿性关节炎中发现MCPIP增加，导致内皮功能障碍。他汀类药物治疗或 MCP-1 中和抗体给药可拮抗 MCPIP 表达，从而减轻内皮功能障碍。
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 kappa B 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.