Hyperoside inhibits the effects induced by oxidized low-density lipoprotein in vascular smooth muscle cells via oxLDL-LOX-1-ERK pathway

Zhang, Zhengyu; Zhang, Dongdong; Du, Bao-Ling; Chen, Zhiqiang

doi:10.1007/s11010-017-3025-x

Cited by 27 publications

(17 citation statements)

References 24 publications

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“…Next, inhibition of MEK by PD98095 cancelled the activation of ERK induced by OxLDL ( Figure 4 D). Lectin-like OxLDL receptor-1 (LOX-1) was identified as a major receptor for the uptake of OxLDL [ 9 ] and activation of ERK pathway was shown to be mediated by LOX-1 [ 28 ]. In our study, the expression of LOX-1 was significantly increased in INS-1 cells ( Figure 4 E), suggesting that OxLDL suppressed ABCA1 transcription via LOX-1/MEK/ERK pathway in INS-1 cells.…”

Section: Resultsmentioning

confidence: 99%

Oxidized LDL Downregulates ABCA1 Expression via MEK/ERK/LXR Pathway in INS-1 Cells

et al. 2021

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Impaired insulin secretion is one of the main causes of type 2 diabetes. Cholesterol accumulation-induced lipotoxicity contributes to impaired insulin secretion in pancreatic beta cells. However, the detailed mechanism in this process remains unclear. In this study, we proved that oxidized low-density lipoprotein (OxLDL) reduced insulin content, decreased PDX-1 expression, and impaired glucose-stimulated insulin secretion (GSIS) in INS-1 cells, which were rescued by addition of high-density lipoprotein (HDL). OxLDL receptors and cholesterol content were increased by OxLDL. Consistently, OxLDL suppressed cholesterol transporter ABCA1 expression and transcription in a dose-dependent and time-dependent manner. Inhibition of MEK by its specific inhibitor, PD98059, altered the effect of OxLDL on ABCA1 transcription and activation of ERK. Next, chromatin immunoprecipitation assay demonstrated that liver X receptor (LXR) could directly bind to ABCA1 promoter and this binding was inhibited by OxLDL. Furthermore, OxLDL decreased the nuclear LXR expression, which was prevented by HDL. LXR-enhanced ABCA1 transcription was suppressed by OxLDL, and the effect was cancelled by mutation of the LXR-binding sites. In summary, our study shows that OxLDL down-regulates ABCA1 expression by MEK/ERK/LXR pathway, leading to cholesterol accumulation in INS-1 cells, which may result in impaired insulin synthesis and GSIS.

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Section: Resultsmentioning

confidence: 99%

Oxidized LDL Downregulates ABCA1 Expression via MEK/ERK/LXR Pathway in INS-1 Cells

et al. 2021

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“…Moreover, ERK1/2 was shown to be activated by ox-LDL in vascular smooth muscle cells and endothelial cells via LOX-1 [66–68]. Inhibition of ERK suppressed cell proliferation in ox-LDL-treated vascular smooth muscle cells [66, 67] and reduced matrix metalloproteinase expression in endothelial cells [68]. These results suggest that the LOX-1/ERK axis may serve as a potential therapeutic target for LDL(-)-mediated atherosclerosis.…”

Section: Discussionmentioning

confidence: 99%

Electronegative LDL from Rabbits Fed with Atherogenic Diet Is Highly Proinflammatory

Chang

Pai

Lai

et al. 2019

Mediators of Inflammation

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Electronegative low-density lipoprotein (LDL(-)) has been found in the plasma of familial hypercholesterolemia and acute myocardial infarction and has been implicated in atherosclerosis and cardiovascular disease. However, less is known about the involvement of LDL(-) in atherosclerosis-related inflammation. This study aims at investigating the inducibility of LDL(-) by atherogenic diet in rabbits and at exploring the proinflammatory potential of the diet-induced LDL(-) in macrophages. Rabbits were fed with an atherogenic diet; LDL was isolated from plasma by NaBr density gradient ultracentrifugation and was then resolved into nLDL and LDL(-) by anion-exchange chromatography. Isolated nLDL and LDL(-) were directly used or incubated with 10 μM CuSO4 for 24 h to produce copper- (Cu-) ox-nLDL and Cu-ox-LDL(-). The effects of these LDLs on inflammation were evaluated in THP-1-derived macrophages. Macrophages were treated with nLDL, LDL(-), and extensively oxidized LDL (ox-LDL), then the levels of interleukin- (IL-) 1β, IL-6, and tumor necrosis factor- (TNF-) α in a culture medium were determined by ELISA, and the levels of total and phosphorylated IκB, p65, p38, JNK, and ERK in cell lysates were determined by Western blotting. The LDL(-) induced significantly higher levels of IL-1β, IL-6, and TNF-α in the medium. The levels of phosphorylated/total IκB, p65, p38, JNK, and ERK were also upregulated by LDL(-). In contrast, nLDL, Cu-ox-nLDL, and Cu-ox-LDL(-) exhibited much less effect. Knockdown of lectin-type oxidized LDL receptor- (LOX-) 1 resulted in significant reduction in LDL(-)-induced IL-1β, IL-6, and TNF-α. In addition, these LDL(-) effects were also markedly attenuated by inhibition of NF-κB and ERK1/2. The data suggested that LDL(-) induced inflammation through LOX-1-, NF-κB-, and ERK1/2-dependent pathways. Taken together, our results show that rabbits fed with atherogenic diet produce a highly proinflammatory LDL(-) that is more potent in inducing inflammation than nLDL and extensively oxidize LDL in macrophages. The results thus provide a novel link between diet-induced hypercholesterolemia and inflammation.

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“…The C-type lectin domain is critical for oxLDL binding. In terms of expression, LOX-1 is ubiquitously expressed in vascular cells, such as endothelial cells (Sawamura et al, 1997), macrophages (Draude et al, 1999), VSMCs (Zhang et al, 2017), cardiomyocytes (Schlüter et al, 2017), and fibroblasts (Liu et al, 2016a). The ubiquitous expression pattern of LOX-1 in cardiovascular cells implicates its important role in regulating cardiovascular pathophysiology.…”

Section: A Cholesterol Uptakementioning

confidence: 99%

Targeting Foam Cell Formation in Atherosclerosis: Therapeutic Potential of Natural Products

et al. 2019

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Hyperoside inhibits the effects induced by oxidized low-density lipoprotein in vascular smooth muscle cells via oxLDL-LOX-1-ERK pathway

Cited by 27 publications

References 24 publications

Oxidized LDL Downregulates ABCA1 Expression via MEK/ERK/LXR Pathway in INS-1 Cells

Oxidized LDL Downregulates ABCA1 Expression via MEK/ERK/LXR Pathway in INS-1 Cells

Electronegative LDL from Rabbits Fed with Atherogenic Diet Is Highly Proinflammatory

Targeting Foam Cell Formation in Atherosclerosis: Therapeutic Potential of Natural Products

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