Activation of m TOR modulates SREBP-2 to induce foam cell formation through increased retinoblastoma protein phosphorylation

Abstract

Aims: Our previous studies demonstrated that inflammation contributes to atherosclerosis through disruption of the low density lipoprotein receptor (LDLr) pathway. However, this effect is overridden by rapamycin, which is an inhibitor of mammalian target of rapamycin (m TOR). This study investigated the role of the m TOR pathway in atherosclerosis in vivo and in vitro. Methods and results: To induce inflammation, we used subcutaneous injection of 10% casein in apolipoprotein E knockout (Apo E KO) mice and lipopolysaccharide stimulation in rat vascular smooth muscle cells (VSMCs). Results showed that inflammation increased lipid accumulation in aortas of Apo E KO mice and in VSMCs, which were correlated with increased expressions of LDLr, sterol regulatory element-binding protein (SREBP) cleavage-activating protein (SCAP), and SREBP-2 as well as with enhanced translocation of SCAP/SREBP-2 complex from the endoplasmic reticulum (ER) to the Golgi. Furthermore, inflammation increased both the percentage of cells in the Sphase of cell cycle and protein expressions of the phosphory-lated forms of retinoblastoma tumour suppressor protein (Rb), m TOR, eukaryotic initiation factor 4E-binding protein 1 (4EBP1), and P70 S6 kinase. After treatment with rapamycin or m TOR si RNA, the activity of the m TOR pathway was blocked. Interestingly, the expression levels of LDLr, SCAP, and SREBP-2 and the translocation of SCAP/SREBP-2 complex from the ER to the Golgi in treated VSMCs were decreased even in the presence of inflammatory stress. Conclusion: Our findings demonstrate for thefirst time that inflammation disrupts LDLr feedback regulation through the activation of the m TOR pathway. Increased m TORC1 activity was found to up-regulate SREBP-2-mediated cholesterol uptake through Rb phosphorylation. © The Author 2013.