标题：Atorvastatin suppresses LPS-induced rapid upregulation of Toll-like receptor 4 and its signaling pathway in endothelial cells
作者：Wang, Ying; Zhang, Ming Xiang; Meng, Xiao; Liu, Fu Qiang; Yu, Guang Sheng; Zhang, Cheng; Sun, Tao; Wang, Xu Ping; Li, Li; Wang, Yuan 更多 作者机构：[Wang, Ying; Zhang, Ming Xiang; Meng, Xiao; Liu, Fu Qiang; Zhang, Cheng; Sun, Tao; Wang, Xu Ping; Li, Li; Wang, Yuan Yuan; Ding, Shi Fang; Yang, Jian 更多
通讯作者地址：[Zhang, Y]Shandong Univ, Qilu Hosp, Key Lab Cardiovasc Remodeling & Funct Res, Chinese Minist Educ,Dept Cardiol, 107 Wen Hua Xi Rd, Jinan 250012, Shan 更多
来源：AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY
关键词：atherosclerosis; inflammation; NF-kappa B
摘要：Wang Y, Zhang MX, Meng X, Liu FQ, Yu GS, Zhang C, Sun T, Wang XP, Li L, Wang YY, Ding SF, Yang JM, Zhang Y. Atorvastatin suppresses LPS-induced rapid upregulation of Toll-like receptor 4 and its signaling pathway in endothelial cells. Am J Physiol Heart Circ Physiol 300: H1743-H1752, 2011. First published February 11, 2011; doi:10.1152/ajpheart.01335.2008.-In the present study, we tested our hypothesis that atorvastatin exerts its anti-inflammation effect via suppressing LPS-induced rapid upregulation of Toll-like receptor 4 (TLR4) mRNA and its downstream p38, ERK, and NF-kappa B signaling pathways in human umbilical-vein endothelial cells (HUVECs) and human aortic endothelial cells (HAECs). TLR4 mRNA expression and its downstream kinase activities induced by LPS alone or atorvastatin + LPS in endothelial cells were quantified using quantitative real-time PCR and enzyme-linked immunosorbent assay. Preincubation of LPS-stimulated endothelial cells with TLR4 siRNA was conducted to identify the target of the anti-inflammatory effects of atorvastatin. Atorvastatin incubation resulted in the reduction of LPS-induced TLR4 mRNA expression. ERK1/2 and P38 MAPK phosphorylation, and NF-kappa B binding activity. Pretreatment with MEK/ERK1/2 inhibitor PD98059 attenuated atorvastatin + LPS-induced NF-kappa B activity but had no effect on P38 MAPK phosphorylation. In contrast, pretreatment with P38 MAPK inhibitor SB203580 resulted in upregulation of atorvastatin + LPS-induced ERK1/2 phosphorylation but had no significant effects on NF-kappa B activity. On the other hand, blocking NF-kappa B with SN50 produced no effects on atorvastatin + [PS-induced ERK1/2 and P38 MARK phosphorylation. Moreover. TLR4 gene silencing produced the same effects as the atorvastatin treatment. In conclusion, atorvastatin downregulated TLR4 mRNA expression by two distinct signaling pathways. First, atorvastatin stabilized I kappa-B alpha, which directly inhibited NF-kappa B activation. Second, atorvastatin inactivated ERK phosphorylation, which indirectly inhibited NF-kappa B activation. Suppression of p38 MAPK by atorvastatin trpregulates ERK but exerts no effect on NF-kappa B.