Rapamycin inhibits ox-LDL-induced inflammation in human endothelial cells in vitro by inhibiting the mTORC2/PKC/c-Fos pathway

• 来源期刊: 中国药理学报（英文版）
• 关键词: atherosclerosis rapamycin endothelial cells ox-LDL ICAM-1 E-selectin mTORC2 PKC c-Fos HUVECs
• 年，卷（期）: 2018,（3）
• 页码范围: 336-344
• 页数: 9页
• 语种: 英文
• DOI: 10.1038/aps.2017.102

摘要

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-LDL-induced adhesion molecule expression and macrophage adhesion to endothelial cells in vitro and the underlying mechanisms.Ox-LDL (6-48 μg/mL) dose-dependently increased the protein levels of two adhesion molecules,intercellular adhesion molecule-1 (ICAM-1) and E-selectin,in human umbilical vein endothelial cells (HUVECs),whereas pretreatment with rapamycin (1-10 μmol/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 μg/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 μg/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.