Journal
ACTA PHARMACOLOGICA SINICA
Volume 39, Issue 3, Pages 336-344Publisher
ACTA PHARMACOLOGICA SINICA
DOI: 10.1038/aps.2017.102
Keywords
atherosclerosis; rapamycin; endothelial cells; ox-LDL; ICAM-1; E-selectin; mTORC2; PKC; c-Fos; HUVECs
Funding
- Natural Science Foundation of Jiangsu Province [BK20122172]
- National Natural Science Foundation of China [81200894, 81471195]
- Priority Academic Program Development of Jiangsu Higher Education Institutions
- Suzhou Medical Key Discipline Project
- Preponderant Clinic Discipline Group Project Fund of the Second Affiliated Hospital of Soochow University [XKQ2015002]
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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.
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