mTOR signaling promotes foam cell formation and inhibits foam cell egress through suppressing the SIRT1 signaling pathway

作者：Zheng, Haixiang; Fu, Yucai; Huang, Yusheng; Zheng, Xinde; Yu, Wei; Wang, Wei^*

来源：Molecular Medicine Reports, 2017, 16(3): 3315-3323.

DOI：10.3892/mmr.2017.7032

• atherosclerosis
• mTOR
• SIRT1 signaling
• monocyte-derived foam cell

Atherosclerosis (AS) is a chronic immunoinflam-matory 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-kappa B (LXR-CCR7/NF-kappa B) 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-kappa B 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, LXR alpha and CCR7 and increased expression of NF-kappa B and its downstream factor tumor necrosis factor-alpha (TNF-alpha) 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, LXR alpha, and CCR7. Conversely, rapamycin deceased TNF-alpha and NF-kappa B activity, the latter of which was further confirmed by immunofluorescence analysis demonstrating increased levels of NF-kappa B 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.

• 出版日期2017-9
• 单位汕头大学