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mTOR signaling promotes foam cell formation and inhibits foam cell egress through suppressing the SIRT1 signaling pathway
Atherosclerosis (AS) is a chronic immuno-inflammatory disease accompanied by dyslipidemia. The authors previously demonstrated that sirtuin 1 (SIRT1) may prevent atherogenesis through influencing the liver X receptor/C-C chemokine receptor type 7/nuclear factor-κB (LXR-CCR7/NF-κB) signaling pathway....
Autores principales: | , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
D.A. Spandidos
2017
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5548025/ https://www.ncbi.nlm.nih.gov/pubmed/28765952 http://dx.doi.org/10.3892/mmr.2017.7032 |
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author | Zheng, Haixiang Fu, Yucai Huang, Yusheng Zheng, Xinde Yu, Wei Wang, Wei |
author_facet | Zheng, Haixiang Fu, Yucai Huang, Yusheng Zheng, Xinde Yu, Wei Wang, Wei |
author_sort | Zheng, Haixiang |
collection | PubMed |
description | Atherosclerosis (AS) is a chronic immuno-inflammatory disease accompanied by dyslipidemia. The authors previously demonstrated that sirtuin 1 (SIRT1) may prevent atherogenesis through influencing the liver X receptor/C-C chemokine receptor type 7/nuclear factor-κB (LXR-CCR7/NF-κB) signaling pathway. Previous studies have suggested a role for mammalian target of rapamycin (mTOR) signaling in the pathogenesis of cardiovascular diseases. The present study investigated the potential association between mTOR signaling and SIRT1-LXR-CCR7/NF-κB signaling (SIRT1 signaling) in AS pathogenesis. To induce foam cell formation, U937 cells were differentiated into macrophages by exposure to phorbol 12-myristate 13-acetate (PMA) for 24 h, followed by treatment with palmitate and oxidized low density lipoprotein for a further 24 h. Oil red O staining revealed a large accumulation of lipid droplets present in foam cells. Western blot analysis demonstrated increased protein levels of phosphorylated (p)-mTOR and its downstream factor p-ribosomal protein S6 kinase (p70S6K). Reverse transcription-quantitative polymerase chain reaction and western blot analyses additionally revealed decreased expression of SIRT1, LXRα and CCR7 and increased expression of NF-κB and its downstream factor tumor necrosis factor-α (TNF-α) in an atherogenetic condition induced by lysophosphatidic acid (LPA). In addition, abundant lipid droplets accumulated in U937-LPA-treated foam cells. Rapamycin, an mTOR inhibitor, suppressed the expression and activity of mTOR and p70S6K, however enhanced expression of SIRT1, LXRα, and CCR7. Conversely, rapamycin deceased TNF-α and NF-κB activity, the latter of which was further confirmed by immunofluorescence analysis demonstrating increased levels of NF-κB present in the cytoplasm compared with the nucleus. The findings of the present study suggest that mTOR signaling promotes foam cell formation and inhibits foam cell egress via suppression of SIRT1 signaling. |
format | Online Article Text |
id | pubmed-5548025 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2017 |
publisher | D.A. Spandidos |
record_format | MEDLINE/PubMed |
spelling | pubmed-55480252017-10-24 mTOR signaling promotes foam cell formation and inhibits foam cell egress through suppressing the SIRT1 signaling pathway Zheng, Haixiang Fu, Yucai Huang, Yusheng Zheng, Xinde Yu, Wei Wang, Wei Mol Med Rep Articles Atherosclerosis (AS) is a chronic immuno-inflammatory disease accompanied by dyslipidemia. The authors previously demonstrated that sirtuin 1 (SIRT1) may prevent atherogenesis through influencing the liver X receptor/C-C chemokine receptor type 7/nuclear factor-κB (LXR-CCR7/NF-κB) signaling pathway. Previous studies have suggested a role for mammalian target of rapamycin (mTOR) signaling in the pathogenesis of cardiovascular diseases. The present study investigated the potential association between mTOR signaling and SIRT1-LXR-CCR7/NF-κB signaling (SIRT1 signaling) in AS pathogenesis. To induce foam cell formation, U937 cells were differentiated into macrophages by exposure to phorbol 12-myristate 13-acetate (PMA) for 24 h, followed by treatment with palmitate and oxidized low density lipoprotein for a further 24 h. Oil red O staining revealed a large accumulation of lipid droplets present in foam cells. Western blot analysis demonstrated increased protein levels of phosphorylated (p)-mTOR and its downstream factor p-ribosomal protein S6 kinase (p70S6K). Reverse transcription-quantitative polymerase chain reaction and western blot analyses additionally revealed decreased expression of SIRT1, LXRα and CCR7 and increased expression of NF-κB and its downstream factor tumor necrosis factor-α (TNF-α) in an atherogenetic condition induced by lysophosphatidic acid (LPA). In addition, abundant lipid droplets accumulated in U937-LPA-treated foam cells. Rapamycin, an mTOR inhibitor, suppressed the expression and activity of mTOR and p70S6K, however enhanced expression of SIRT1, LXRα, and CCR7. Conversely, rapamycin deceased TNF-α and NF-κB activity, the latter of which was further confirmed by immunofluorescence analysis demonstrating increased levels of NF-κB present in the cytoplasm compared with the nucleus. The findings of the present study suggest that mTOR signaling promotes foam cell formation and inhibits foam cell egress via suppression of SIRT1 signaling. D.A. Spandidos 2017-09 2017-07-18 /pmc/articles/PMC5548025/ /pubmed/28765952 http://dx.doi.org/10.3892/mmr.2017.7032 Text en Copyright: © Zheng et al. This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License (https://creativecommons.org/licenses/by-nc-nd/4.0/) , which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made. |
spellingShingle | Articles Zheng, Haixiang Fu, Yucai Huang, Yusheng Zheng, Xinde Yu, Wei Wang, Wei mTOR signaling promotes foam cell formation and inhibits foam cell egress through suppressing the SIRT1 signaling pathway |
title | mTOR signaling promotes foam cell formation and inhibits foam cell egress through suppressing the SIRT1 signaling pathway |
title_full | mTOR signaling promotes foam cell formation and inhibits foam cell egress through suppressing the SIRT1 signaling pathway |
title_fullStr | mTOR signaling promotes foam cell formation and inhibits foam cell egress through suppressing the SIRT1 signaling pathway |
title_full_unstemmed | mTOR signaling promotes foam cell formation and inhibits foam cell egress through suppressing the SIRT1 signaling pathway |
title_short | mTOR signaling promotes foam cell formation and inhibits foam cell egress through suppressing the SIRT1 signaling pathway |
title_sort | mtor signaling promotes foam cell formation and inhibits foam cell egress through suppressing the sirt1 signaling pathway |
topic | Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5548025/ https://www.ncbi.nlm.nih.gov/pubmed/28765952 http://dx.doi.org/10.3892/mmr.2017.7032 |
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