Exogenous supplement of N-acetylneuraminic acid ameliorates atherosclerosis in apolipoprotein E-deficient mice

Guo, Shoudong; Tian, Hua; Dong, Rongrong; Yang, Ning; Zhang, Ying; Yao, Shutong; Li, Yongjun; Zhou, Yixiao; Si, Yanna; Qin, Shucun

doi:10.1016/j.atherosclerosis.2016.05.032

Cited by 44 publications

(55 citation statements)

References 29 publications

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“…Additionally, lipid reduction is one of the most important strategies for the treatment of CVD with hyperlipidaemia. A previous study by our group indicated that a combination of quercetin and N ‐acetylneuraminic acid or N ‐acetylneuraminic acid alone could significantly reduce triglycerides and cholesterol in apoE‐deficient mice to which a high‐fat diet was provided 49. The in vitro results of this study showed QA's attractive ability to improve cholesterol efflux.…”

Section: Discussionmentioning

confidence: 51%

“…The results obtained in ‘the therapeutic model’ demonstrated that QA significantly increased the N‐acetylneuraminic acid level compared with quercetin. The underlying mechanisms may be associated to: (1) the higher antioxidant activity of QA compared with quercetin, which could reduce ROS‐induced desialylation, (2) N ‐acetylneuraminic acid linked to QA may be incorporated into the cell under the action of sialyltransferase; and (3) QA may be hydrolysed by neuraminidase, and then, N‐acetylneuraminic acid and quercetin will exert synergic effects in their free form, as we reported in a previous study 49. As reviewed by Gokmen et al ., both sialyltransferase and neuraminidase activities are increased in CVD patients 5, and therefore, the superiority of QA over quercetin becomes more prominent.…”

Section: Discussionmentioning

confidence: 71%

“…Previous studies have indicated that flavonoids may activate ABCA1 by up‐regulation of peroxisome proliferator‐activated receptor γ and liver X receptor α 21; another research study showed that quercetin enhances ABCA1 expression through a p38‐dependent pathway in macrophages 48. Our previous data indicated that both quercetin and exogenous N ‐acetylneuraminic acid could improve RCT‐related protein expression in apoE‐deficient mice 49.…”

Section: Discussionmentioning

confidence: 82%

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Synthesis and cardiovascular protective effects of quercetin 7‐O‐sialic acid

Tian

Liu

Qin

et al. 2016

J Cellular Molecular Medi

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Oxidative stress and inflammation play important roles in the pathogenesis of cardiovascular disease (CVD). Oxidative stress‐induced desialylation is considered to be a primary step in atherogenic modification, and therefore, the attenuation of oxidative stress and/or inflammatory reactions may ameliorate CVD. In this study, quercetin 7‐O‐sialic acid (QA) was synthesized aiming to put together the cardiovascular protective effect of quercetin and the recently reported anti‐oxidant and anti‐atherosclerosis functions of N‐acetylneuraminic acid. The biological efficacy of QA was evaluated in vitro in various cellular models. The results demonstrated that 50 μM QA could effectively protect human umbilical vein endothelial cells (HUVEC, EA.hy926) against hydrogen peroxide‐ or oxidized low‐density lipoprotein‐induced oxidative damage by reducing the production of reactive oxygen species. QA attenuated hydrogen peroxide‐induced desialylation of HUVEC and lipoproteins. QA decreased lipopolysaccharide‐induced secretion of tumour necrosis factor‐α (TNF‐α) and monocyte chemoattractant protein‐1 (MCP‐1), and it significantly reduced the expression of intercellular adhesion molecule‐1, vascular cell adhesion molecule‐1, TNF‐α and MCP‐1. Furthermore, QA effectively promoted cholesterol efflux from Raw 264.7 macrophages to apolipoprotein A‐1 and high‐density lipoprotein by up‐regulating ATP‐binding cassette transporter A1 and G1, respectively. Results indicated that the novel compound QA exhibited a better capacity than quercetin for anti‐oxidation, anti‐inflammation, cholesterol efflux promotion and biomolecule protection against desialylation and therefore could be a candidate compound for the prevention or treatment of CVD.

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Section: Discussionmentioning

confidence: 51%

Section: Discussionmentioning

confidence: 71%

Section: Discussionmentioning

confidence: 82%

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Synthesis and cardiovascular protective effects of quercetin 7‐O‐sialic acid

Tian

Liu

Qin

et al. 2016

J Cellular Molecular Medi

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“…It is noteworthy that recent studies indicated that quercetin decreases hyperlipidaemia in different high-fat diet fed animals [3–6]. …”

Section: Introductionmentioning

confidence: 99%

“…An in vitro study has indicated that quercetin may activate ATP-binding cassette (ABC) A1 by up-regulating peroxisome proliferator-activated receptor γ (PPAR-γ) and liver X receptor α (LXR-α) [8], while other research showed that quercetin enhances ABCA1 expression through a p38-dependent pathway in macrophages [9]. Our previous data indicated that quercetin improves the expression of RCT-related proteins in apolipoprotein E-deficient ( apoE −/− ) mice [3]. However, there is little known about the in vivo biological effects and mechanisms of quercetin on RCT.…”

Section: Introductionmentioning

confidence: 99%

Quercetin improves macrophage reverse cholesterol transport in apolipoprotein E-deficient mice fed a high-fat diet

Cui

Hou

et al. 2017

Lipids Health Dis

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BackgroundQuercetin, one of the most widely distributed flavonoids in plants, has been demonstrated to reduce hyperlipidaemia and atherosclerotic lesion formation. Reverse cholesterol transport (RCT) plays a crucial role in exporting cholesterol from peripheral cells, which is one mechanism utilized in the prevention and treatment of atherosclerosis. The aim of this study is to investigate whether quercetin reduces lipid accumulation by improving RCT in vivo.MethodsApolipoprotein E-deficient mice fed a high-fat diet were used to investigate the effect of quercetin on RCT by an isotope tracing method, and the underlying mechanisms were clarified by molecular techniques.ResultsThese novel results demonstrated that quercetin significantly improved [3H]-cholesterol transfer from [3H]-cholesterol-loaded macrophages to the plasma (approximately 34% increase), liver (30% increase), and bile (50% increase) and finally to the feces (approximately 40% increase) for excretion in apolipoprotein E-deficient mice fed a high-fat diet. Furthermore, quercetin markedly increased the cholesterol accepting ability of plasma and high-density lipoprotein (HDL) and dramatically decreased the content of malondialdehyde in plasma and oxidized phosphocholine carried by HDL. Therefore, the underlying mechanisms of quercetin in improving RCT may be partially due to the elevated cholesterol accepting ability of HDL, the increased expression levels of proteins related to RCT, such as ATP-binding cassettes (ABC) A1 and G1, and the improved antioxidant activity of HDL.ConclusionQuercetin accelerates RCT in an atherosclerosis model, which is helpful in clarifying the lipid-lowering effect of quercetin.

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N‐acetylneuraminic acid modulates SQSTM1/p62 sialyation‐mediated ubiquitination degradation contributing to vascular endothelium dysfunction in experimental atherosclerosis mice

Chen,

Qiu,

Chen

et al. 2023

IUBMB Life

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Sialic acid (SIA) has been reported to be a risk factor for atherosclerosis (AS) due to its high plasma levels in such patients. However, the effect of increasing SIA in circulation on endothelial function during AS progression remains unclear. In the present study, ApoE−/− mice and endothelial cells line (HUVEC cells) were applied to investigate the effect of SIA on AS progression and its potential molecular mechanism. In vivo, mice were injected intraperitoneally with Neu5Ac (main form of SIA) to keep high‐level SIA in circulation. ORO, H&E, and Masson staining were applied to detect the plaque progression. In vitro, HUVECs were treated with Neu5Ac at different times, CCK‐8, RT‐PCR, western blot, and immunoprecipitation methods were used to analyze its effects on endothelial function and the potential involved mechanism. Results from the present study showed that high plasma levels of Neu5Ac in ApoE−/− mice could aggravate the plaque areas as well as increase necrotic core areas and collagen fiber contents. Remarkably, Neu5Ac levels in circulation displayed a positive correlation with AS plaque areas. Furthermore, results from HUVECs showed that Neu5Ac inhibited cells viability in a time/dose‐dependent manner, by then induced the activation of inflammation makers such as ICAM‐1 and IL‐1β. Mechanism study showed that the activation of excessive autophagy medicated by SQSTM1/p62 displayed an important role in endothelium inflammatory injury. Neu5Ac could modify SQSTM1/p62 as a sialylation protein, and then increase its level with ubiquitin binding, further inducing ubiquitination degradation and being involved in the excessive autophagy pathway. Inhibition of sialylation by P‐3Fax‐Neu5Ac, a sialyltransferase inhibitor, reduced the binding of SQSTM1/p62 to ubiquitin. Together, these findings indicated that Neu5Ac increased SQSTM1/p62‐ubiquitin binding through sialylation modification, thereby inducing excessive autophagy and subsequent endothelial injury. Inhibition of SQSTM1/p62 sialylation might be a potential strategy for preventing such disease with high levels of Neu5Ac in circulation.

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Exogenous supplement of N-acetylneuraminic acid ameliorates atherosclerosis in apolipoprotein E-deficient mice

Cited by 44 publications

References 29 publications

Synthesis and cardiovascular protective effects of quercetin 7‐O‐sialic acid

Synthesis and cardiovascular protective effects of quercetin 7‐O‐sialic acid

Quercetin improves macrophage reverse cholesterol transport in apolipoprotein E-deficient mice fed a high-fat diet

N‐acetylneuraminic acid modulates SQSTM1/p62 sialyation‐mediated ubiquitination degradation contributing to vascular endothelium dysfunction in experimental atherosclerosis mice

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