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2000
Volume 33, Issue 8
  • ISSN: 0929-8673
  • E-ISSN: 1875-533X
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Abstract

Background

Atherosclerosis is a chronic disease characterized by the increased infiltration and retention of LDL particles in arterial walls. There are several mechanisms underlying atherogenesis, with the pro-atherogenic modifications of LDL playing a significant role. One such modification of native LDL is desialylation, which is characterized by the removal of terminal sialic acid from ApoB-100 glycans that induces critical changes in the overall functionality of the LDL particle.

Aims

The aim of this study was to model the desialylation of native LDL in mice, resembling a phenomenon previously observed in atherosclerotic patients.

Objective

LDL desialylation was induced in C57BL/6J mice the injection of exogenous neuraminidase. The degree of LDL desialylation and its duration were assessed. The impact of LDL desialylation on blood lipid levels was evaluated. Furthermore, the morphological alterations in the aorta during LDL desialylation in the bloodstream were examined.

Methods

The control group of C57BL/6J mice received saline injections, while the experimental group underwent a single injection of IgG-conjugated neuraminidase. The LDL sialic acid levels were assessed 1-7 days post-injection using the Warren method and normalized to total protein content measured the Lowry method. A similar protocol was followed for the subchronic administration of the IgG-neuraminidase conjugate over a 6-week period. The blood lipid profiles were analyzed using commercial kits. The atherosclerotic plaque burden in the mouse aorta was quantified using Oil Red O and hematoxylin-eosin staining.

Results

A single administration of 20 mU IgG-neuraminidase conjugate resulted in decreased LDL sialic acid levels for 5 days, gradually recovering by days 6-7. Subchronic administration maintained reduced LDL sialic acid levels for up to 2 months. Notably, sustained LDL desialylation was associated with elevated LDL cholesterol levels.

Conclusion

A sustained desialylation of LDL in C57BL/6J mice was achieved through subchronic administration of IgG-conjugated neuraminidase. This study provides an approach for sustained LDL desialylation in mice. Further studies using apolipoprotein E knockout mice and LDL desialylation will reveal the role of this process in the occurrence and development of atherosclerosis.

© 2026 The Author(s). Published by Bentham Science Publishers.
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References

  1. PoredošP. Endothelial dysfunction in the pathogenesis of atherosclerosis.Int. Angiol.200221210911610.1007/978‑1‑4612‑6071‑4_84/COVER12110769
     [Google Scholar]
  2. SchwenkeD.C. CarewT.E. Initiation of atherosclerotic lesions in cholesterol-fed rabbits. II. Selective retention of LDL vs. selective increases in LDL permeability in susceptible sites of arteries.Arteriosclerosis19899690891810.1161/01.ATV.9.6.9082590068
     [Google Scholar]
  3. KashirskikhD.A. GuoS. PanyodS. ChicherinaN.R. EktaM.B. BogatyrevaA.I. GrechkoA. A novel insight into the nature of modified low-density lipoproteins and their role in atherosclerosis.Vessel Plus20237310.20517/2574‑1209.2022.35
     [Google Scholar]
  4. PoznyakA.V. NikiforovN.G. MarkinA.M. KashirskikhD.A. MyasoedovaV.A. GerasimovaE.V. OrekhovA.N. Overview of OxLDL and its impact on cardiovascular health: focus on atherosclerosis.Front. Pharmacol.20211161378010.3389/fphar.2020.61378033510639
     [Google Scholar]
  5. GersztenR.E. Garcia-ZepedaE.A. LimY.C. YoshidaM. DingH.A. GimbroneM.A.Jr LusterA.D. LuscinskasF.W. RosenzweigA. MCP-1 and IL-8 trigger firm adhesion of monocytes to vascular endothelium under flow conditions.Nature1999398672971872310.1038/1954610227295
     [Google Scholar]
  6. BoisvertW.A. SantiagoR. CurtissL.K. TerkeltaubR.A. A leukocyte homologue of the IL-8 receptor CXCR-2 mediates the accumulation of macrophages in atherosclerotic lesions of LDL receptor-deficient mice.J. Clin. Invest.1998101235336310.1172/JCI11959435307
     [Google Scholar]
  7. RochaV.Z. LibbyP. Obesity, inflammation, and atherosclerosis.Nat. Rev. Cardiol.20096639940910.1038/nrcardio.2009.5519399028
     [Google Scholar]
  8. ShaoB. HanB. ZengY. SuD. LiuC. The roles of macrophage autophagy in atherosclerosis.Acta Pharmacol. Sin.201637215015610.1038/aps.2015.8726750103
     [Google Scholar]
  9. GrewalT. BartlettA. BurgessJ.W. PackerN.H. StanleyK.K. Desialylated LDL uptake in human and mouse macrophages can be mediated by a lectin receptor.Atherosclerosis1996121115116310.1016/0021‑9150(95)05715‑38678920
     [Google Scholar]
  10. SukhorukovV. GudeljI. Pučić-BakovićM. ZakievE. OrekhovA. KontushA. LaucG. Glycosylation of human plasma lipoproteins reveals a high level of diversity, which directly impacts their functional properties.Biochim. Biophys. Acta Mol. Cell Biol. Lipids20191864564365310.1016/j.bbalip.2019.01.00530641224
     [Google Scholar]
  11. TertovV.V. NikonovaE.Y. Nifant’evN.E. BovinN.V. OrekhovA.N. Human plasma trans-sialidase donor and acceptor specificity.Biochemistry200267890891310.1023/A:101991870492012223090
     [Google Scholar]
  12. MehrK. WithersS.G. Mechanisms of the sialidase and trans-sialidase activities of bacterial sialyltransferases from glycosyltransferase family 80.Glycobiology201626435335910.1093/glycob/cwv10526582604
     [Google Scholar]
  13. GrachevaE.V. SamovilovaN.N. GolovanovaN.K. Il’inskayaO.P. TararakE.M. MalyshevP.P. KukharchukV.V. ProkazovaN.V. Sialyltransferase activity of human plasma and aortic intima is enhanced in atherosclerosis.Biochim. Biophys. Acta Mol. Basis Dis.20021586112312810.1016/S0925‑4439(01)00093‑X11781157
     [Google Scholar]
  14. DeminaE.P. SmutovaV. PanX. FougeratA. GuoT. ZouC. ChakrabertyR. SnarrB.D. ShiaoT.C. RoyR. OrekhovA.N. MiyagiT. LaffargueM. SheppardD.C. CairoC.W. PshezhetskyA.V. Neuraminidases 1 and 3 trigger atherosclerosis by desialylating low-density lipoproteins and increasing their uptake by macrophages.J. Am. Heart Assoc.2021104e01875610.1161/JAHA.120.01875633554615
     [Google Scholar]
  15. MezentsevA. BezsonovE. KashirskikhD. BaigM.S. EidA.H. OrekhovA. Proatherogenic sialidases and desialylated lipoproteins: 35 years of research and current state from bench to bedside.Biomedicines20219660010.3390/biomedicines906060034070542
     [Google Scholar]
  16. TertovV.V. KaplunV.V. SobeninI.A. BoytsovaE.Y. BovinN.V. OrekhovA.N. Human plasma trans-sialidase causes atherogenic modification of low density lipoprotein.Atherosclerosis2001159110311510.1016/S0021‑9150(01)00498‑111689212
     [Google Scholar]
  17. GlanzV.Y. KashirskikhD.A. GrechkoA.V. YetS.F. SobeninI.A. OrekhovA.N. Sialidase activity in human blood serum has a distinct seasonal pattern: A pilot study.Biology20209818410.3390/biology908018432708035
     [Google Scholar]
  18. LibbyP. AlroyJ. PereiraM.E. LibbyP. AlroyJ. PereiraM.E.A. A neuraminidase from Trypanosoma cruzi removes sialic acid from the surface of mammalian myocardial and endothelial cells.J. Clin. Invest.198677112713510.1172/JCI1122663080470
     [Google Scholar]
  19. SoongG. MuirA. GomezM.I. WaksJ. ReddyB. PlanetP. SinghP.K. KanekoY. WolfgangM.C. HsiaoY.S. TongL. PrinceA. Bacterial neuraminidase facilitates mucosal infection by participating in biofilm production.J. Clin. Invest.200611682297230510.1172/JCI2792016862214
     [Google Scholar]
  20. NishikawaT. ShimizuK. TanakaT. KurodaK. TakayamaT. YamamotoT. HanadaN. HamadaY. Bacterial neuraminidase rescues influenza virus replication from inhibition by a neuraminidase inhibitor.PLoS One201279e4537110.1371/journal.pone.004537123028967
     [Google Scholar]
  21. AlipovV.I. SukhorukovV.N. KaragodinV.P. GrechkoA.V. OrekhovA.N. Chemical composition of circulating native and desialylated low density lipoprotein: what is the difference?Vessel Plus2017110711510.20517/2574‑1209.2017.20
     [Google Scholar]
  22. OrekhovA.N. MyasoedovaV.A. Low density lipoprotein-induced lipid accumulation is a key phenomenon of atherogenesis at the arterial cell level.Vessel Plus20192019310.20517/2574‑1209.2018.80
     [Google Scholar]
  23. OrekhovA.N. SukhorukovV.N. NikiforovN.G. KubekinaM.V. SobeninI.A. FoxxK.K. PintusS. StegmaierP. StelmashenkoD. KelA. PoznyakA.V. WuW.K. KasianovA.S. MakeevV.Y. ManabeI. OishiY. Signaling pathways potentially responsible for foam cell formation: cholesterol accumulation or inflammatory response what is first?Int. J. Mol. Sci.2020218271610.3390/ijms2108271632295185
     [Google Scholar]
  24. TertovV.V. Bittolo-BonG. SobeninI.A. CazzolatoG. OrekhovA.N. AvogaroP. Naturally occurring modified low density lipoproteins are similar if not identical: more electronegative and desialylated lipoprotein subfractions.Exp. Mol. Pathol.199562316617210.1006/exmp.1995.10188612720
     [Google Scholar]
  25. HermansonG.T. Bioconjugate Techniques.3rd edBioconjugate Tech20131114610.1016/C2009‑0‑64240‑9
     [Google Scholar]
  26. YardeniT. EckhausM. MorrisH.D. HuizingM. Hoogstraten-MillerS. Retro-orbital injections in mice.Lab Anim.201140515516010.1038/laban0511‑15521508954
     [Google Scholar]
  27. RislingT.E. CaulkettN.A. FlorenceD. Open-drop anesthesia for small laboratory animals.Can. Vet. J.201253329930222942448
     [Google Scholar]
  28. OrekhovA.N. TertovV.V. SobeninI.A. SmirnovV.N. ViaD.P. GuevaraJ.Jr GottoA.M.Jr MorrisettJ.D. Sialic acid content of human low density lipoproteins affects their interaction with cell receptors and intracellular lipid accumulation.J. Lipid Res.199233680581710.1016/S0022‑2275(20)41506‑81512508
     [Google Scholar]
  29. TertovV.V. SobeninI.A. GabbasovZ.A. PopovE.G. JaakkolaO. SolakiviT. NikkariT. SmirnovV.N. OrekhovA.N. Multiple-modified desialylated low density lipoproteins that cause intracellular lipid accumulation. Isolation, fractionation and characterization.Lab. Invest.19926756656751434544
     [Google Scholar]
  30. SobeninI.A. TertovV.V. OrekhovA.N. Optimization of the assay for sialic acid determination in low density lipoprotein.J. Lipid Res.199839112293229910.1016/S0022‑2275(20)32485‑89799816
     [Google Scholar]
  31. WaterborgJ.H. The Lowry Method for Protein Quantitation.Springer Protocols Handbooks200971010.1007/978‑1‑59745‑198‑7_2
     [Google Scholar]
  32. Andrés-ManzanoM.J. AndrésV. DoradoB. Oil Red O and hematoxylin and eosin staining for quantification of atherosclerosis burden in mouse aorta and aortic root.Methods Mol. Biol.20151339859910.1007/978‑1‑4939‑2929‑0_526445782
     [Google Scholar]
  33. YuL. PengJ. MineoC. Lipoprotein sialylation in atherosclerosis: Lessons from mice.Front. Endocrinol.20221395316510.3389/fendo.2022.95316536157440
     [Google Scholar]
  34. PoznyakA.V. KashirskikhD.A. PostnovA.Y. PopovM.A. SukhorukovV.N. OrekhovA.N. Sialic acid as the potential link between lipid metabolism and inflammation in the pathogenesis of atherosclerosis.Braz. J. Med. Biol. Res.202356e1297210.1590/1414‑431x2023e1297238088673
     [Google Scholar]
  35. AngataT. VarkiA. Chemical diversity in the sialic acids and related alpha-keto acids: An evolutionary perspective.Chem. Rev.2002102243947010.1021/cr000407m11841250
     [Google Scholar]
  36. TertovV.V. SobeninI.A. OrekhovA.N. Characterization of desialylated low-density lipoproteins which cause intracellular lipid accumulation.Int. J. Tissue React.19921441551621478792
     [Google Scholar]
  37. HörkköS. HuttunenK. KervinenK. KesäniemiA. Decreased clearance of uraemic and mildly carbamylated low-density lipoprotein.Eur. J. Clin. Invest.199424210511310.1111/j.1365‑2362.1994.tb00974.x8206079
     [Google Scholar]
  38. BucalaR. MakitaZ. VegaG. GrundyS. KoschinskyT. CeramiA. VlassaraH. Modification of low density lipoprotein by advanced glycation end products contributes to the dyslipidemia of diabetes and renal insufficiency.Proc. Natl. Acad. Sci.199491209441944510.1073/pnas.91.20.94417937786
     [Google Scholar]
  39. LinJ. LinJ. Low-density lipoprotein: biochemical and metabolic characteristics and its pathogenic mechanism.Apolipoproteins, Triglycerides Cholestintechopen2020868668687210.5772/intechopen.86872
     [Google Scholar]
  40. TertovV.V. OrekhovA.N. Metabolism of native and naturally occurring multiple modified low density lipoprotein in smooth muscle cells of human aortic intima.Exp. Mol. Pathol.199764312714510.1006/exmp.1997.22169439479
     [Google Scholar]
  41. OrekhovA.N. TertovV.V. MukhinD.N. MikhailenkoI.A. Modification of low density lipoprotein by desialylation causes lipid accumulation in cultured cells: Discovery of desialylated lipoprotein with altered cellular metabolism in the blood of atherosclerotic patients.Biochem. Biophys. Res. Commun.1989162120621110.1016/0006‑291X(89)91982‑72751649
     [Google Scholar]
  42. OrekhovA.N. TertovV.V. PokrovskyS.N. Adamova IYu MartsenyukO.N. LyakishevA.A. SmirnovV.N. Blood serum atherogenicity associated with coronary atherosclerosis. Evidence for nonlipid factor providing atherogenicity of low-density lipoproteins and an approach to its elimination.Circ. Res.198862342142910.1161/01.RES.62.3.4213342473
     [Google Scholar]
  43. OrekhovA.N. TertovV.V. MukhinD.N. Desialylated low density lipoprotein naturally occurring modified lipoprotein with atherogenic potency.Atherosclerosis1991862-315316110.1016/0021‑9150(91)90211‑K1872910
     [Google Scholar]
  44. BergmannK. Non-HDL cholesterol and evaluation of cardiovascular disease risk.EJIFCC2010213646727683375
     [Google Scholar]
  45. OppiS. LüscherT.F. SteinS. Mouse models for atherosclerosis research :Which is my line?Front. Cardiovasc. Med.201964610.3389/fcvm.2019.0004631032262
     [Google Scholar]
  46. SunT. ChenM. ShenH. PingYin FanL. ChenX. WuJ. XuZ. ZhangJ. Predictive value of LDL/HDL ratio in coronary atherosclerotic heart disease.BMC Cardiovasc. Disord.202222127310.1186/s12872‑022‑02706‑635715736
     [Google Scholar]
  47. Guyard-DangremontV. DesrumauxC. GambertP. LallemantC. LagrostL. Phospholipid and cholesteryl ester transfer activities in plasma from 14 vertebrate species. Relation to atherogenesis susceptibility.Comp. Biochem. Physiol. B Biochem. Mol. Biol.1998120351752510.1016/S0305‑0491(98)10038‑X9787811
     [Google Scholar]
  48. VéniantM.M. WithycombeS. YoungS.G. Lipoprotein size and atherosclerosis susceptibility in Apoe(-/-) and Ldlr(-/-) mice.Arterioscler. Thromb. Vasc. Biol.200121101567157010.1161/hq1001.09778011597927
     [Google Scholar]
  49. IshibashiS. BrownM.S. GoldsteinJ.L. GerardR.D. HammerR.E. HerzJ. Hypercholesterolemia in low density lipoprotein receptor knockout mice and its reversal by adenovirus-mediated gene delivery.J. Clin. Invest.199392288389310.1172/JCI1166638349823
     [Google Scholar]
  50. von HoltK. LebrunS. StinnW. ConroyL. WallerathT. SchleefR. Progression of atherosclerosis in the Apo E−/− model: 12-Month exposure to cigarette mainstream smoke combined with high-cholesterol/fat diet.Atherosclerosis2009205113514310.1016/j.atherosclerosis.2008.11.03119144336
     [Google Scholar]
  51. WesterterpM. van der HoogtC.C. de HaanW. OffermanE.H. Dallinga-ThieG.M. JukemaJ.W. HavekesL.M. RensenP.C.N. Cholesteryl ester transfer protein decreases high-density lipoprotein and severely aggravates atherosclerosis in APOE*3-Leiden mice.Arterioscler. Thromb. Vasc. Biol.200626112552255910.1161/01.ATV.0000243925.65265.3c16946130
     [Google Scholar]
  52. SmithJ.D. BreslowJ.L. The emergence of mouse models of atherosclerosis and their relevance to clinical research.J. Intern. Med.199724229910910.1046/j.1365‑2796.1997.00197.x9279286
     [Google Scholar]
  53. DaughertyA. RateriD.L. Development of experimental designs for atherosclerosis studies in mice.Methods200536212913810.1016/j.ymeth.2004.11.00815893934
     [Google Scholar]
  54. FriedewaldW.T. LevyR.I. FredricksonD.S. Estimation of the concentration of low-density lipoprotein cholesterol in plasma, without use of the preparative ultracentrifuge.Clin. Chem.197218649950210.1093/clinchem/18.6.4994337382
     [Google Scholar]
  55. Sanchez-MunizF.J. BastidaS. Do not use the Friedewald formula to calculate LDL-cholesterol in hypercholesterolaemic rats.Eur. J. Lipid Sci. Technol.2008110429530110.1002/ejlt.200700280
     [Google Scholar]
  56. de SilvaH.V. Más-OlivaJ. TaylorJ.M. MahleyR.W. Identification of apolipoprotein B-100 low density lipoproteins, apolipoprotein B-48 remnants, and apolipoprotein E-rich high density lipoproteins in the mouse.J. Lipid Res.19943571297131010.1016/S0022‑2275(20)39973‑97964191
     [Google Scholar]
  57. World Health Organization (WHO) Available online: https://www.who.int/ (accessed on 29 August 2023).
  58. HetheringtonI. Totary-JainH. Anti-atherosclerotic therapies: Milestones, challenges, and emerging innovations.Mol. Ther.202230103106311710.1016/j.ymthe.2022.08.02436065464
     [Google Scholar]
  59. SurkovaR. KashirskikhD. SobeninI. ZotovaU. MarkinA. GlanzV. OrekhovA. Resialylation of low- density lipoproteins: A promising way to reduce low-density lipoproteins atherogenicity.Atherosclerosis2023379S7410.1016/j.atherosclerosis.2023.06.286
     [Google Scholar]
  60. LindbergG. Resialylation of sialic acid deficit vascular endothelium, circulating cells and macromolecules may counteract the development of atherosclerosis: A hypothesis.Atherosclerosis2007192224324510.1016/j.atherosclerosis.2007.03.01117420020
     [Google Scholar]
  61. BocquetO. WahartA. SarazinT. VincentE. SchneiderC. FougeratA. GayralS. HenryA. BlaiseS. Romier-CrouzetB. BoulagnonC. JaissonS. GilleryP. BennasrouneA. SarteletH. LaffargueM. MartinyL. DucaL. MauriceP. Adverse effects of oseltamivir phosphate therapy on the liver of ldlr−/− mice without any benefit on atherosclerosis and thrombosis.J. Cardiovasc. Pharmacol.202177566067210.1097/FJC.000000000000100233760798
     [Google Scholar]
  62. FooteC.A. GhiaroneT. Ramirez-PerezF.I. KluserA.R. GrunewaldZ.I. JurrissenT.J. BrownS.M. BenderS.B. Manrique-AcevedoC. AroorA.R. The targeted inhibition of neuraminidase reverses endothelial glycocalyx degradation and improves endothelial function in type 2 diabetes.The FASEB J.201931S1527.16527.1610.1096/fasebj.2019.33.1_supplement.527.16
     [Google Scholar]
  63. Betancourt-CortesE. Betancourt-CortesE. FooteC. Ramirez-PerezF. JurrisenT. PowerG. Morales-QuiñonesM. Lazo-FernandezY. AugenreichM. Manrique-AcevedoC. Neuraminidase-1 inhibition reduces arterial stiffness and improves endothelial function in diabetic mice.American Physiology Summit 2023 Meeting202338S11610.1152/physiol.2023.38.S1.5796078
     [Google Scholar]
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Mouse Model of Low-density Lipoprotein Desialylation In Vivo
Curr. Med. Chem. 33, 1523 (2026); https://doi.org/10.2174/0109298673294745240528092506
/content/journals/cmc/10.2174/0109298673294745240528092506
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  • Article Type:     Research Article
Keyword(s): Atherosclerosis; desialylation; desLDL; low-density lipoproteins; neuraminidase; sialic acid

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