Toll-like receptor 4 is up-regulated by mTOR activation during THP-1 macrophage foam cells formation

Yu, Miao; Kang, Xiaomin; Xue, Hong; Yin, Hongchao

doi:10.1093/abbs/gmr093

Cited by 28 publications

(17 citation statements)

References 40 publications

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“…Moreover, mTOR inhibition during DES transplantation caused endothelial dysfunction and inflammation and promoted thrombus formation31. OxLDL, one of the culprits of atherosclerosis, could active mTOR during THP-1 macrophage foam cells formation and in rabbit femoral SMCs3233. However, we found that oxLDL inhibited mTOR activity in VECs in this study.…”

Section: Discussioncontrasting

confidence: 60%

An activator of mTOR inhibits oxLDL-induced autophagy and apoptosis in vascular endothelial cells and restricts atherosclerosis in apolipoprotein E-/- mice

Peng

Meng

Wang

et al. 2014

Sci Rep

145

114

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Oxidized low-density lipoprotein (oxLDL) inhibits mammalian target of rapamycin (mTOR) and induces autophagy and apoptosis in vascular endothelial cells (VECs) that play very critical roles for the cardiovascular homostasis. We recently defined 3-benzyl-5-((2-nitrophenoxy) methyl)-dihydrofuran-2(3H)-one (3BDO) as a new activator of mTOR. Therefore, we hypothesized that 3BDO had a protective role in VECs and thus stabilized atherosclerotic lesions in apolipoprotein E-/- (apoE-/-) mice. Our results showed that oxLDL inhibited the activity of mTOR and increased the protein level of autophagy-related 13 (ATG13) and its dephosphorylation, thus inducing autophagy in human umbilical vein endothelial cells (HUVECs). All of these effects were strongly inhibited by 3BDO. In vivo experiments confirmed that 3BDO activated mTOR and decreased the protein level of ATG13 in the plaque endothelium of apoE-/- mice. Importantly, 3BDO did not affect the activity of mTOR and autophagy in macrophage cell line RAW246.7 and vascular smooth muscle cells of apoE-/- mice, but suppressed plaque endothelial cell death and restricted atherosclerosis development in the mice. 3BDO protected VECs by activating mTOR and thus stabilized atherosclerotic lesions in apoE-/- mice.

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Section: Discussioncontrasting

confidence: 60%

An activator of mTOR inhibits oxLDL-induced autophagy and apoptosis in vascular endothelial cells and restricts atherosclerosis in apolipoprotein E-/- mice

Peng

Meng

Wang

et al. 2014

Sci Rep

145

114

View full text Add to dashboard Cite

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“…49 ox-LDL could active mTOR during the formation of THP-1 macrophage foam cells and in rabbit femoral smooth muscle cells. 50,51 By contrast, a recent report indicates that ox-LDL inhibited mTOR activity in vascular endothelial cells and suggests that the effect of ox-LDL on the mTOR pathway might be cell-type specific. 52 Consistent with the previous study, this study showed that ox-LDL decreased the phosphorylation of mTOR in HUVECs ( Figure 4D).…”

Section: ■ Discussionmentioning

confidence: 92%

In Vitro and in Vivo Atheroprotective Effects of Gossypetin against Endothelial Cell Injury by Induction of Autophagy

Lin

2015

Chem. Res. Toxicol.

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Oxidized low-density lipoprotein (ox-LDL) contributes to the pathogenesis of atherosclerosis by promoting vascular endothelial cell injury.Gossypetin, a naturally occurring hexahydroxyflavone, has been shown to possess antimutagenic, antioxidant, antimicrobial, and antiatherosclerotic effects. In this study, the atheroprotective role of gossypetin was examined in endothelial cells. The protective effect of gossypetin against ox-LDL-induced injury in human umbilicalvein endothelial cells (HUVECs) was first noted at 0.1−0.5 μM. Gossypetin showed potential in reducing ox-LDL-dependent apoptosis, as demonstrated by morphological and biochemical features, including formation of apoptotic bodies,distribution of hypodiploid phase, and activation of caspase-3. Next, the ox-LDL induced formation of acidic vesicular organelles and the upregulation of autophagyrelated genes (LC3 and Beclin-1) were enhanced by gossypetin. Gossypetin triggered autophagic flux was further confirmed by an increase in the level of LC3-II under pretreatment conditions with an autophagy inhibitor, chloroquine (CQ). In addition, silencing Beclin-1 inhibited both the gossypetin-mediated protective affects and the autophagic process. Molecular data indicated that the autophagic effect of gossypetin might be mediated via the class III PI3K/Beclin-1 and PTEN/class I PI3K/Akt signaling cascades, as demonstrated by the use of a class III PI3K inhibitor, 3-methyladenine (3-MA), and a PTEN inhibitor, SF1670. Finally, gossypetin improved atherosclerotic lesions and endothelial injury in vivo. These data imply that gossypetin upregulates the autophagic pathway, which led to subsequent reduction of ox-LDL-induced atherogenic endothelial cell injury and apoptosis, and provide a new mechanism for the antiatherosclerotic activity of gossypetin.

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“…Therefore, TLR4 might contribute to the progression of atherosclerosis. Furthermore, ox-LDL increased mRNA and protein levels of TLR4 in U937 promonocytic leukemia cells and macrophages [35,36]. We found that ox-LDL increased the expression of TLR4 in cultured mast cells, accompanied by the induction of inflammatory cytokine.…”

Section: Discussionmentioning

confidence: 92%

Oxidized Low-Density Lipoprotein Induces Inflammatory Responses in Cultured Human Mast Cells Via Toll-Like Receptor 4

Meng

Yan

Deng

et al. 2013

Cell Physiol Biochem

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Background/Aims: Oxidized low-density lipoprotein (ox-LDL) is a powerful atherogen. Toll-like receptor 4 (TLR4) has a pathophysiological role in regulating inflammatory responses and atherosclerosis. Mast cells can infiltrate into the atheromatous plaque and secrete various pro-inflammatory cytokines, which significantly amplify the atherogenic processes and promote plaque vulnerability. Small interfering RNA (siRNA) is an effective method to silence the target genes. We evaluated whether ox-LDL-induced inflammation depended in part on the activation of TLR4-dependent signaling pathways in a cultured human mast cell line (HMC-1). Method: HMC-1 cells were cultured, and treated with ox-LDL, TLR4-specific siRNA, or inhibitors of phosphorylation of mitogen-activated protein kinase (MAPKs), and nuclear factor-κB (NF-κB), a critical mediator of inflammation. The expression of monocyte chemoattractant protein-1 (MCP-1), tumor necrosis factor-a (TNF-a) and interleukin 6 (IL-6) was measured subsequently. Results: Ox-LDL increased the expression of TLR4 and secretion of MCP-1, TNF-a and IL-6. Moreover, ox-LDL stimulated the translocation of NF-κB, from the cytoplasm to nucleus. Additionally, phosphorylation of MAPK was greatly increased. These ox-LDL-induced alterations were significantly attenuated by pretreatment with TLR4-specific siRNA. Conclusion: Ox-LDL induced inflammatory responses in cultured HMC-1 cells including NF-κB nuclear translocation and phosphorylation of MAPKs, a process mediated in part by TLR4.

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Toll-like receptor 4 is up-regulated by mTOR activation during THP-1 macrophage foam cells formation

Cited by 28 publications

References 40 publications

An activator of mTOR inhibits oxLDL-induced autophagy and apoptosis in vascular endothelial cells and restricts atherosclerosis in apolipoprotein E-/- mice

An activator of mTOR inhibits oxLDL-induced autophagy and apoptosis in vascular endothelial cells and restricts atherosclerosis in apolipoprotein E-/- mice

In Vitro and in Vivo Atheroprotective Effects of Gossypetin against Endothelial Cell Injury by Induction of Autophagy

Oxidized Low-Density Lipoprotein Induces Inflammatory Responses in Cultured Human Mast Cells Via Toll-Like Receptor 4

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