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

Abstract

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) dose-dependently 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.

Statins use and its impact in EGFR‐TKIs resistance to prolong the survival of lung cancer patients: A Cancer registry cohort study in Taiwan

“…Intercellular adhesion molecule‐1 (ICAM‐1) and E‐selection are both common adhesion molecules that play important roles in inflammation. The LDL inflammation mechanism may interact with the environment as a carcinogen in lung cancer formation 34 . Other reports have shown that lipid accumulation and expression of CXCL16 and Nephrin are induced by oxidized LDL 35 .…”

eNOS-Nitric Oxide System Contributes to a Novel Antiatherogenic Effect of Leonurine via Inflammation Inhibition and Plaque Stabilization

“…(Hansson et al, 2015) Here we induced endothelial cell inflammation by challenging HUVECs with ox-LDL according to literature. (Sun et al, 2018) and then treated cells with LEO. LEO at a concentration of 50μM or less did not influence cell viability and showed no toxicity.…”

Rapamycin: A Bacteria-Derived Immunosuppressant That Has Anti-atherosclerotic Effects and Its Clinical Application

“…RAPA has been found to attenuate monocyte chemotactic protein-1 expression in the aortic arch of apoE-deficient mice fed an atherogenic diet, a finding that illustrates that RAPA has anti-migratory effects on macrophages (Castro et al, 2004). Additionally, RAPA can dose-dependently decrease the ox-LDL-induced expression of ICAM-1 and E-selectin and inhibit the adhesion of monocytes to human umbilical vein-endothelial cells through suppressing the activation of MTORC2, and then inhibiting PKC phosphorylation and c-fos expression (Sun et al, 2017). Moreover, TNF-α, an inflammatory cytokine, can drive adhesion molecule expression through activating the Raf-1-Merk1/2-ERK1/2 pathway (Roberts and Der, 2007).…”