Advertisement

Lipids

, Volume 47, Issue 10, pp 995–1000 | Cite as

Pluronic Block Copolymers Inhibit Low Density Lipoprotein Self-Association

  • Alexandra A. Melnichenko
  • Denis V. Aksenov
  • Veronika A. Myasoedova
  • Oleg M. Panasenko
  • Alexander A. Yaroslavov
  • Igor A. Sobenin
  • Yuri V. BobryshevEmail author
  • Alexander N. Orekhov
Original Article

Abstract

Little is known about exogenous inhibitors of low-density lipoprotein (LDL) aggregation. The search for nontoxic and bioavailable inhibitors of LDL aggregation is of interest, especially considering that the suppression of the aggregation of LDL might represent a therapeutic approach. We hypothesized that amphiphilic copolymers of propylene oxide and ethylene oxide, the so-called Pluronic block copolymers, can be used to influence the aggregation of LDL. In this work we used Pluronic® P85, L61 and F68. A comparative study of the effects of Pluronic block copolymers with various hydrophilic–lipophilic properties on the aggregation process of LDL showed that Pluronic copolymers with strong hydrophobic properties (P85 and L61) at concentrations close to or greater than the respective critical concentration of micelle formation inhibited the aggregation process of LDL; however, the “hydrophilic” Pluronic F68 had no effect on the aggregation of LDL at any concentration. Thus, the study demonstrated for the first time that Pluronic® block copolymers inhibit LDL self-association. The possibility of modulating the aggregation of LDL by various Pluronic copolymers can be regarded as a prerequisite in the creation of new types of anti-atherosclerotic drugs.

Keywords

Low density lipoproteins LDL Aggregation Atherosclerosis Pluronic block copolymers 

Abbreviations

ApoA

Apolipoprotein

ApoA-I

High-density lipoprotein apolipoprotein

BSA

Bovine serum albumin

HDL

High-density lipoprotein(s)

EO

Ethylene oxide

LDL

Low-density lipoprotein(s)

PO

Propylene oxide

VLDL

Very low-density lipoprotein(s)

Notes

Acknowledgments

This study was supported by the Russian Ministry of Education and Science.

Conflict of interest

No conflict of interest is declared by the authors.

References

  1. 1.
    Anitschkow NN, Chatalov S (1913) Über experimentelle Cholesterinsteatose und ihre Bedeutung für die Entstehung einiger pathologischer Prozesse. Zentralbl Allg Pathol 24:1–9Google Scholar
  2. 2.
    Smith EB (1974) The relationship between plasma and tissue lipids in human atherosclerosis. Adv Lpid Res 12:1–49Google Scholar
  3. 3.
    Mahley RW, Innerarity TL, Weisgraber KH, Oh SY (1979) Altered metabolism (in vivo and in vitro) of plasma lipoproteins after selective modification of lysine residues of apoproteins. J Clin Invest 64:743–750PubMedCrossRefGoogle Scholar
  4. 4.
    Alaupovic P (1971) Apolipoproteins and lipoproteins. Atherosclerosis 13:141–146PubMedCrossRefGoogle Scholar
  5. 5.
    Bobryshev YV (2006) Monocyte recruitment and foam cell formation in atherosclerosis. Micron 37:208–222PubMedCrossRefGoogle Scholar
  6. 6.
    Bates SR, Wissler RW (1976) Effect of hyperlipemic serum on cholesterol accumulation in monkey aortic medial cells. Biochim Biophys Acta 450:78–88PubMedCrossRefGoogle Scholar
  7. 7.
    Ross R, Harker L (1976) Hyperlipidemia and atherosclerosis. Science 193:1094–1100PubMedCrossRefGoogle Scholar
  8. 8.
    Goldstein JL, Ho YK, Basu SK, Brown MS (1979) Binding site on macrophages that mediates uptake and degradation of acetylated low density lipoprotein, producing massive cholesterol deposition. Proc Natl Acad Sci USA 76:333–337PubMedCrossRefGoogle Scholar
  9. 9.
    Fogelman AM, Shechter I, Seager J, Hokom M, Child JS, Edwards PA (1980) Malondialdehyde alteration of low density lipoproteins leads to cholesteryl ester accumulation in human monocyte-macrophages. Proc Natl Acad Sci USA 77:2214–2218PubMedCrossRefGoogle Scholar
  10. 10.
    Khoo JC, Miller E, McLoughlin P, Steinberg B (1990) Prevention of low density lipoprotein aggregation by high density lipoprotein or apolipoprotein A-I. J Lipid Res 31:645–652PubMedGoogle Scholar
  11. 11.
    Lopes-Virella MF, Klein RL, Lyons TJ, Stevenson HC, Witztum JL (1988) Glycosylation of low-density lipoprotein enhances cholesteryl ester synthesis in human monocyte-derived macrophages. Diabetes 37:550–557PubMedCrossRefGoogle Scholar
  12. 12.
    Tertov VV, Sobenin IA, Gabbasov ZA, Popov EG, Orekhov AN (1989) Lipoprotein aggregation as an essential condition of intracellular lipid caused by modified low density lipoproteins. Biochem Biophys Res Commun 16:489–494CrossRefGoogle Scholar
  13. 13.
    Bancells C, Benítez S, Jauhiainen M, Ordóñez-Llanos J, Kovanen PT, Villegas S, Sánchez-Quesada JL, Oörni K (2009) High binding affinity of electronegative LDL to human aortic proteoglycans depends on its aggregation level. J Lipid Res 50:446–455PubMedCrossRefGoogle Scholar
  14. 14.
    Talbot RM, del Rio JD, Weinberg PD (2003) Effect of fluid mechanical stresses and plasma constituents on aggregation of LDL. J Lipid Res 44:837–845PubMedCrossRefGoogle Scholar
  15. 15.
    Brunelli R, Balogh G, Costa G, De Spirito M, Greco G, Mei G, Nicolai E, Vigh L, Ursini F, Parasassi T (2010) Estradiol binding prevents ApoB-100 misfolding in electronegative LDL(−). Biochemistry 49:7297–7302PubMedCrossRefGoogle Scholar
  16. 16.
    Tertov VV, Kaplun VV, Sobenin IA, Orekhov AA (1998) Low-density lipoprotein modification occurring in human plasma possible mechanism of in vivo lipoprotein desialylation as a primary step of atherogenic modification. Atherosclerosis 138:183–195PubMedCrossRefGoogle Scholar
  17. 17.
    Tertov VV, Sobenin IA, Gabbasov ZA, Popov EG, Jaakkola O, Solakivi T, Nikkari T, Smirnov VN, Orekhov AN (1992) Multiple-modified desialylated low density lipoproteins that cause intracellular lipid accumulation. Isolation, fractionation and characterization. Lab Invest 67:665–675PubMedGoogle Scholar
  18. 18.
    Parasassi T, De Spirito M, Mei G, Brunelli R, Greco G, Lenzi L, Maulucci G, Nicolai E, Papi M, Arcovito G, Tosatto SC, Ursini F (2008) Low density lipoprotein misfolding and amyloidogenesis. FASEB J 22:2350–2356PubMedCrossRefGoogle Scholar
  19. 19.
    Bancells C, Villegas S, Blanco FJ, Benítez S, Gállego I, Beloki L, Pérez-Cuellar M, Ordóñez-Llanos J, Sánchez-Quesada JL (2010) Aggregated electronegative low density lipoprotein in human plasma shows a high tendency toward phospholipolysis and particle fusion. J Biol Chem 285:32425–32435PubMedCrossRefGoogle Scholar
  20. 20.
    Bancells C, Benítez S, Ordóñez-Llanos J, Öörni K, Kovanen PT, Milne RW, Sánchez-Quesada JL (2011) Immunochemical analysis of the electronegative LDL subfraction shows that abnormal N-terminal apolipoprotein B conformation is involved in increased binding to proteoglycans. J Biol Chem 286:1125–1133PubMedCrossRefGoogle Scholar
  21. 21.
    Greco G, Balogh G, Brunelli R, Costa G, De Spirito M, Lenzi L, Mei G, Ursini F, Parasassi T (2009) Generation in human plasma of misfolded, aggregation-prone electronegative low density lipoprotein. Biophys J 97:628–635PubMedCrossRefGoogle Scholar
  22. 22.
    Llorente-Cortés V, Badimon L (2005) LDL receptor-related protein and the vascular wall: implications for atherothrombosis. Arterioscler Thromb Vasc Biol 25:497–504PubMedCrossRefGoogle Scholar
  23. 23.
    Llorente-Cortés V, Otero-Viñas M, Camino-López S, Costales P, Badimon L (2006) Cholesteryl esters of aggregated LDL are internalized by selective uptake in human vascular smooth muscle cells. Arterioscler Thromb Vasc Biol 26:117–123PubMedCrossRefGoogle Scholar
  24. 24.
    Oörni K, Pentikäinen MO, Ala-Korpela M, Kovanen PT (2000) Aggregation, fusion, and vesicle formation of modified low density lipoprotein particles: molecular mechanisms and effects on matrix interactions. J Lipid Res 41:1703–1714PubMedGoogle Scholar
  25. 25.
    Plihtari R, Kovanen PT, Öörni K (2011) Acidity increases the uptake of native LDL by human monocyte-derived macrophages. Atherosclerosis 217:401–406PubMedCrossRefGoogle Scholar
  26. 26.
    Lähdesmäki K, Öörni K, Alanne-Kinnunen M, Jauhiainen M, Hurt-Camejo E, Kovanen PT (2012) Acidity and lipolysis by group V secreted phospholipase A(2) strongly increase the binding of apoB-100-containing lipoproteins to human aortic proteoglycans. Biochim Biophys Acta 1821:257–267PubMedCrossRefGoogle Scholar
  27. 27.
    Vinogradov SV, Batrakova EV, Li S, Kabanov AV (2004) Mixed polymer micelles of amphiphilic and cationic copolymers for delivery of antisense oligonucleotides. J Drug Target 12:517–526PubMedCrossRefGoogle Scholar
  28. 28.
    Batrakova EV, Li S, Alakhov VY, Miller DW, Kabanov AV (2003) Optimal structure requirements for pluronic block copolymers in modifying P-glycoprotein drug efflux transporter activity in bovine brain microvessel endothelial cells. Farmacol Exp Ther 304:845–854CrossRefGoogle Scholar
  29. 29.
    Alakhova DY, Rapoport NY, Batrakova EV, Timoshin AA, Li S, Nicholls D, Alakhov VY, Kabanov AV (2010) Differential metabolic responses to pluronic in MDR and non-MDR cells: a novel pathway for chemosensitization of drug resistant cancers. J Controlled Release 142:89–100CrossRefGoogle Scholar
  30. 30.
    Batrakova EV, Li S, Li Y, Alakhov VY, Kabanov AV (2004) Effect of pluronic P85 on ATPase activity of drug efflux transporters. Pharm Res 21:2226–2233PubMedCrossRefGoogle Scholar
  31. 31.
    Batrakova EV, Li S, Li Y, Alakhov VY, Elmquist WF, Kabanov AV (2004) Distribution kinetics of a micelle-forming block copolymer Pluronic P85. J Controlled Release 100:389–397CrossRefGoogle Scholar
  32. 32.
    Johnston TP, Baker JC, Hall D, Jamal AS, Emeson EE, Palmer WK (1999) Potential downregulation of HMG-CoA reductase following chronic administration of P-407 to C57BL/6 mice. J Cardiovasc Pharmacol 34:831–842PubMedCrossRefGoogle Scholar

Copyright information

© AOCS 2012

Authors and Affiliations

  • Alexandra A. Melnichenko
    • 1
  • Denis V. Aksenov
    • 2
  • Veronika A. Myasoedova
    • 1
    • 2
  • Oleg M. Panasenko
    • 2
  • Alexander A. Yaroslavov
    • 3
  • Igor A. Sobenin
    • 2
  • Yuri V. Bobryshev
    • 2
    • 4
    Email author
  • Alexander N. Orekhov
    • 1
    • 2
  1. 1.Institute of General Pathology and PathophysiologyRussian Academy of Medical SciencesMoscowRussia
  2. 2.Skolkovo Innovative Centre, Institute for Atherosclerosis ResearchRussian Academy of Natural SciencesMoscowRussia
  3. 3.Department of ChemistryM.V. Lomonosov Moscow State UniversityMoscowRussia
  4. 4.Faculty of Medicine, School of Medical Sciences, St Vincent’s Hospital SydneyUniversity of New South WalesKensingtonAustralia

Personalised recommendations