机构：[1]Department of Neurology, Second Affiliated Hospital of Soochow University, Suzhou 215004, China[2]Department of Neurosurgery, First Affiliated Hospital of Soochow University, Suzhou 215006, China[3]Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases and Institute of Neuroscience, Soochow University, Suzhou 215123, China[4]Department of Neurology, First Hospital of Handan City, Handan 056002, China
Rapamycin and its derivative possess anti-atherosclerosis activity, but its effects on adhesion molecule expression and macrophage adhesion to endothelial cells during atherosclerosis remain unclear. In this study we explored the effects of rapamycin on ox-LDLinduced adhesion molecule expression and macrophage adhesion to endothelial cells in vitro and the underlying mechanisms. Ox-LDL (6-48 mu g/mL) dose-dependently increased the protein levels of two adhesion molecules, intercellular adhesion molecule-1 (ICAM1) and E-selectin, in human umbilical vein endothelial cells (HUVECs), whereas pretreatment with rapamycin (1-10 mu mol/L) dosedependently inhibited ox-LDL-induced increase in the adhesion molecule expression and macrophage adhesion to endothelial cells. Knockdown of mTOR or rictor, rather than raptor, mimicked the effects of rapamycin. Ox-LDL (100 mu g/mL) time-dependently increased PKC phosphorylation in HUVECs, which was abolished by rapamycin or rictor siRNA. Pretreatment with PKC inhibitor staurosporine significantly reduced ox-LDL-stimulated adhesion molecule expression and macrophage adhesion to endothelial cells, whereas pretreatment with PKC activator PMA/TPA attenuated the inhibitory effect of rapamycin on adhesion molecule expression. Ox-LDL (100 mu g/mL) time-dependently increased c-Fos levels in HUVECs, and pretreatment with rapamycin or rictor siRNA significantly decreased expression of c-Fos. Knockdown of c-Fos antagonized ox-LDL-induced adhesion molecule expression and macrophage adhesion to endothelial cells. Our results demonstrate that rapamycin reduces ox-LDL-stimulated adhesion molecule expression and macrophage adhesion to endothelial cells by inhibiting mTORC2, but not mTORC1, and mTORC2 acts through the PKC/c-Fos signaling pathway.
基金：
This study was supported by a grant from the Natural SciThis study was supported by a grant from the Natural Science
Foundation of Jiangsu Province (BK20122172 to Yan-ling.
ZHANG), the National Natural Science Foundation of China
(81200894 to Yan-ling ZHANG, 81471195 to Yong-jun CAO),
a project funded by the Priority Academic Program Development
of Jiangsu Higher Education Institutions and Suzhou
Medical Key Discipline Project (to Chun-feng LIU), and support
from the Preponderant Clinic Discipline Group Project
Fund of the Second Affiliated Hospital of Soochow University
(XKQ2015002).
第一作者机构：[1]Department of Neurology, Second Affiliated Hospital of Soochow University, Suzhou 215004, China[4]Department of Neurology, First Hospital of Handan City, Handan 056002, China
共同第一作者：
通讯作者：
通讯机构：[1]Department of Neurology, Second Affiliated Hospital of Soochow University, Suzhou 215004, China[3]Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases and Institute of Neuroscience, Soochow University, Suzhou 215123, China
推荐引用方式(GB/T 7714)：
Juan-juan SUN,Xiao-wei YIN,Hui-hui LIU,et al.Rapamycin inhibits ox-LDL-induced inflammation in human endothelial cells in vitro by inhibiting the mTORC2/PKC/c-Fos pathway[J].ACTA PHARMACOLOGICA SINICA.2018,39(3):336-344.doi:10.1038/aps.2017.102.
APA：
Juan-juan SUN,Xiao-wei YIN,Hui-hui LIU,Wen-xiu DU,Lu-yao SHI...&Yan-lin ZHANG.(2018).Rapamycin inhibits ox-LDL-induced inflammation in human endothelial cells in vitro by inhibiting the mTORC2/PKC/c-Fos pathway.ACTA PHARMACOLOGICA SINICA,39,(3)
MLA：
Juan-juan SUN,et al."Rapamycin inhibits ox-LDL-induced inflammation in human endothelial cells in vitro by inhibiting the mTORC2/PKC/c-Fos pathway".ACTA PHARMACOLOGICA SINICA 39..3(2018):336-344
医学