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Activation of mTOR 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 (mTOR). This study investigated the role of the mTOR 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 (ApoE KO) mice and lipopolysaccharide stimulation in rat vascular smooth muscle cells (VSMCs). Results showed that inflammation increased lipid accumulation in aortas of ApoE 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 S phase of cell cycle and protein expressions of the phosphorylated forms of retinoblastoma tumour suppressor protein (Rb), mTOR, eukaryotic initiation factor 4E-binding protein 1 (4EBP1), and P70 S6 kinase. After treatment with rapamycin or mTOR siRNA, the activity of the mTOR 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 the first time that inflammation disrupts LDLr feedback regulation through the activation of the mTOR pathway. Increased mTORC1 activity was found to up-regulate SREBP-2-mediated cholesterol uptake through Rb phosphorylation.

journal_name

Cardiovasc Res

journal_title

Cardiovascular research

authors

Ma KL,Liu J,Wang CX,Ni J,Zhang Y,Wu Y,Lv LL,Ruan XZ,Liu BC

doi

10.1093/cvr/cvt203

subject

Has Abstract

pub_date

2013-12-01 00:00:00

pages

450-60

issue

eissn

0008-6363

issn

1755-3245

pii

cvt203

journal_volume

100

pub_type

杂志文章

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