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Activation of mTOR modulates SREBP-2 to induce foam cell formation through increased retinoblastoma protein phosphorylation.
Activation of mTOR modulates SREBP-2 to induce foam cell formation through increased retinoblastoma protein phosphorylation.
- Source :
-
Cardiovascular research [Cardiovasc Res] 2013 Dec 01; Vol. 100 (3), pp. 450-60. Date of Electronic Publication: 2013 Sep 25. - Publication Year :
- 2013
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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.<br />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.<br />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.
- Subjects :
- Adaptor Proteins, Signal Transducing
Animals
Aorta enzymology
Aorta pathology
Aortic Diseases genetics
Aortic Diseases pathology
Apolipoproteins E deficiency
Apolipoproteins E genetics
Atherosclerosis genetics
Atherosclerosis pathology
Carrier Proteins metabolism
Cell Cycle Proteins
Cells, Cultured
Cholesterol metabolism
Disease Models, Animal
Endoplasmic Reticulum metabolism
Eukaryotic Initiation Factors
Foam Cells drug effects
Foam Cells pathology
Golgi Apparatus metabolism
Inflammation genetics
Inflammation pathology
Intracellular Signaling Peptides and Proteins metabolism
Male
Mechanistic Target of Rapamycin Complex 1
Membrane Proteins metabolism
Mice
Mice, Inbred C57BL
Mice, Knockout
Multiprotein Complexes metabolism
Muscle, Smooth, Vascular drug effects
Muscle, Smooth, Vascular pathology
Phosphoproteins metabolism
Phosphorylation
Protein Kinase Inhibitors pharmacology
RNA Interference
Rats
Receptors, LDL metabolism
Ribosomal Protein S6 Kinases, 70-kDa metabolism
S Phase
Signal Transduction
TOR Serine-Threonine Kinases antagonists & inhibitors
TOR Serine-Threonine Kinases genetics
Transfection
Aortic Diseases enzymology
Atherosclerosis enzymology
Foam Cells enzymology
Inflammation enzymology
Muscle, Smooth, Vascular enzymology
Retinoblastoma Protein metabolism
Sterol Regulatory Element Binding Protein 2 metabolism
Sterol Regulatory Element Binding Proteins metabolism
TOR Serine-Threonine Kinases metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1755-3245
- Volume :
- 100
- Issue :
- 3
- Database :
- MEDLINE
- Journal :
- Cardiovascular research
- Publication Type :
- Academic Journal
- Accession number :
- 24068000
- Full Text :
- https://doi.org/10.1093/cvr/cvt203