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Федеральное государственное бюджетное учреждение науки
"Институт токсикологии Федерального медико-биологического агентства"
(ФГБУН ИТ ФМБА России)

Институт теоретической и экспериментальной биофизики Российской академии наук.

ООО "ИЦ КОМКОН".




Адрес редакции и реквизиты

199406, Санкт-Петербург, ул.Гаванская, д. 49, корп.2

ISSN 1999-6314

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«
Vol. 13, Art. 76 (pp. 900-922)    |    2012       
»

MACROPHAGES AND LIPOPROTEIN METABOLISM IN ATHEROSCLEROTIC LESION
Nikiforov Nikita1,2,4, Gratchev Alexei1,2, Sobenin Igor2, Orekhov Alexander2,3, and Julia Kzhyhskowska1,2

1Medical Faculty Mannheim, Ruprecht-Karls University of Heidelberg, Mannheim, Germany (Theodor-Kutzer Ufer 1-3, 68167 Mannheim, Germany, Tel: +49 621 383 2440, Fax: +49 621 383 3815, E-Mail: julia.kzhyshkowska@umm.de); 2Institute of General Pathology and Pathophysiology, Russian Academy of Medical Sciences, Moscow, Russia; 3Institute for Atherosclerosis Research, Skolkovo Innovative Centre; 4Moscow Institute of Physics and Technology (State University).



Brief summary

Atherosclerosis is one of the most life-threatening human disorders leading to myocardial infarction, unstable angina, sudden cardiac death, and ischemic stroke. Currently it is established that atherosclerosis is a chronic inflammatory disorder characterised by the development of lesions in intima of major arteries. Key role in the development of atherosclerosis play pathological cross-talk between plasma lipoproteins and cells of intima, such as monocytes/macrophages, resulting in the development of foamy cells that constitute a major component of atherosclerotic plaque. In our review we focus on the major cellular and molecular processes leading to the formation and accumulation of foamy cells: increased transmigration of monocytes into sub-endothelial sites of inflammation, activation of macrophages, modifications of lipoproteins, different types of uptake of native and associated lipoproteins (endocytosis, phagocytosis, and less-investigated – patocytosis), as well as participation of different molecular systems in the reverse cholesterol transport in macrophages. Special attention is given to the recent data indicating that scavenger receptors participate not only in the uptake of modified lipoproteins, but also in the reverse cholesterol transport. In conclusion, we discuss most relevant open questions in our understanding of the mechanism and functional consequences of macrophage/lipoprotein interactions: which receptor systems are used for the recognition and internalisation of aggregated lipoproteins, what are the mechanisms of intracellular processing of associated lipoproteins, and how associated lipoproteins affect functional programming of macrophages.


Key words

atherosclerosis, lipoprotein, endocytosis, phagocytosis, scavenger receptor, monocyte, macrophage, inflammation.





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Reference list

1. Update on lipids, inflammation and atherothrombosis. Badimon L, Storey RF, Vilahur G. 2011 r., Thromb Haemost., T. 1, str. S34-42.


2. Lipoproteins, Platelets, and Atherothrombosis. Badimón L, Vilahur G, Padró T. 2009 r., Rev Esp Cardiol., T. 62(10), str. 1161-78.


3. Inflammation, endoplasmic reticulum stress, autophagy, and the monocyte chemoattractant protein-1/CCR2 pathway. Kolattukudy PE, Niu J. 2012 r., Circ Res., T. 110(1), str. 174-89.


4. Monocyte chemoattractant protein-1 (MCP-1): an overview. Deshmane SL, Kremlev S, Amini S, Sawaya BE. 2009 r., J Interferon Cytokine Res., T. 29(6), str. 313-26.


5. Leukocyte influx in atherosclerosis. Galkina E, Ley K. 2007 r., Curr Drug Targets., T. 8(12), str. 1239-48.


6. Monocyte-endothelial cell interactions in the development of atherosclerosis. Mestas J, Ley K. 2008 r., Trends Cardiovasc Med., T. 18(6), str. 228-32.


7. Microparticles, vascular function, and atherothrombosis. Rautou PE, Vion AC, Amabile N, Chironi G, Simon A, Tedgui A, Boulanger CM. 2011 r., Circ Res., T. 109(5), str. 593-606.


8. Macrophages in the pathogenesis of atherosclerosis. Moore KJ, Tabas I. 2011 r., Cell., T. 145(3), str. 341-55.


9. Monocytes as a diagnostic marker of cardiovascular diseases. Gratchev A, Sobenin I, Orekhov A, Kzhyshkowska J. 2012 r., Immunobiology, T. 217, str. 476-482.


10. Expression of the VEP13 antigen (CD16) on native human alveolar macrophages and cultured blood monocytes. Baumgartner I, Scheiner O, Holzinger C, Boltz-Nitulescu G, Klech H, Lassmann H, Rumpold H, Förster O, Kraft D. 1988 r., Immunobiology, T. 177(3), str. 317-26.


11. Transcriptional profiling reveals developmental relationship and distinct biological functions of CD16+ and CD16- monocyte subsets. Ancuta P, Liu KY, Misra V, Wacleche VS, Gosselin A, Zhou X, Gabuzda D. 2009 r., BMC Genomics, T. 10, str. 403.


12. CD14CD16 monocyte subset levels in heart failure patients. Barisione C, Garibaldi S, Ghigliotti G, Fabbi P, Altieri P, Casale MC, Spallarossa P, Bertero G, Balbi M, Corsiglia L, Brunelli C. 2010 r., Dis Markers., T. 28(2), str. 115-24.


13. Increased subpopulations of CD16(+) and CD56(+) blood monocytes in patients with active Crohn's disease. Grip O, Bredberg A, Lindgren S, Henriksson G. 2007 r., Inflamm Bowel Dis., T. 13(5), str. 566-72.


14. Different functions of monocyte subsets in familial hypercholesterolemia: potential function of CD14+ CD16+ monocytes in detoxification of oxidized LDL. Mosig S, Rennert K, Krause S, Kzhyshkowska J, Neunübel K, Heller R, Funke H. 2009 r., FASEB J., T. 23(3), str. 866-74.


15. Monocyte and macrophage dynamics during atherogenesis. Ley K, Miller YI, Hedrick CC. 2011 r., Arterioscler Thromb Vasc Biol., T. 31(7), str. 1506-16.


16. Obstructive sleep apnea: an emerging risk factor for atherosclerosis. Drager LF, Polotsky VY, Lorenzi-Filho G. 2011 r., Chest., T. 140(2), str. 534-42.


17. Inflammatory mechanisms in atherosclerosis. Hansson. 2009 r., J Thromb Haemost., T. 1, str. 328-31.


18. Lipoproteins, macrophage function, and atherosclerosis: beyond the foam cell? Rader DJ, Puré E. 2005 r., Cell Metab., T. 1(4), str. 223-30.


19. Alternative versus classical activation of macrophages. Goerdt S, Politz O, Schledzewski K, Birk R, Gratchev A, Guillot P, Hakiy N, Klemke CD, Dippel E, Kodelja V, Orfanos CE. 1999 r., Pathobiology, T. 67(5-6), str. 222-6.


20. Monocyte and macrophage heterogeneity. Gordon S, Taylor PR. 2005 r., Nat Rev Immunol., T. 5(12), str. 953-64.


21. Alternative activation of macrophages: immune function and cellular biology. Varin A, Gordon S. 2009 r., Immunobiology, T. 214(7), str. 630-41.


22. Antagonistic regulation of macrophage phenotype by M-CSF and GM-CSF: Implication in atherosclerosis. Brochérioua I, Maouchea S, Duranda H, Braunersreutherc V, Naourb G, Gratchevd A, Koskasa F, Machc F, Kzhyshkowska J,Ninioa E. 2011 r., Atherosclerosis, T. 214, str. 316-324.


23. Alternatively Activated Macrophages Differentially Express Fibronectin and Its Splice Variants and the Extracellular Matrix Protein bIG-H3. Gratchev A, Guillot p, Hakiy N, Politz O, Orfanos E, Schledzewski K, Goerdt S. 2001 : b.n., 2001 r., Scand. J. Immunol, T. 53, str. 386-392.


24. Alternative activation of macrophages: mechanism and functions. Gordon S, Martinez FO. 2010 r., Immunity., T. 32(5), str. 593-604.


25. Stabilin-1, a homeostatic scavenger. Kzhyshkowska, J., Gratchev, A., Goerdt, S. 2006 r., J. Cell Mol. Med., T. 10, str. 635–649.


26. M1 and M2 can be re-polarized by Th2 or Th1 cytokines, respectively, and respond to exogenous danger signals. GratchevA, Kzhyshkowska J, Kothe K, Muller-Molinet I, Kannookadan S, Utikal J, Goerdt S. 2006 r., Immunobiology, T. 211, str. 473-486.


27. Interleukin-4 and dexamethasone counterregulate extracellular matrix remodelling and phagocytosis in type-2 macrophages. Gratchev A, Kzhyshkowska J, Utikal J, Goerdt S. 2005 r., Scand J Immunol., T. 61(1), str. 10-17.


28. Novel function of alternatively activated macrophages: stabilin-1-mediated clearance of SPARC. Kzhyshkowska J, Workman G, Cardó-Vila M, Arap W, Pasqualini R, Gratchev A, Krusell L, Goerdt S, Sage EH. 2006 r., J Immunol., T. 176(10), str. 5825-32.


29. Phosphatidylinositide 3-kinase activity is required for stabilin-1-mediated endosomal transport of acLDL. Kzhyshkowska J, Gratchev A, Brundiers H, Mamidi S, Krusell L, Goerdt S. 2005 r., Immunobiology., T. 210(2-4), str. 161-73.


30. Multifunctional receptor stabilin-1 in homeostasis and disease. Kzhyshkowska, J. 2010 r., ScientificWorldJournal., T. 10, str. 2039-53.


31. Role of macrophage scavenger receptors in atherosclerosis. Kzhyshkowska J, Neyen C, Gordon S. 2012 r., Immunobiology, T. 217, str. 492-502.


32. Induction of intracellular cytokine production in human monocytes/macrophages stimulated with ligands of pattern recognition receptors. Mytar B, Gawlicka M, Szatanek R, Wołoszyn M, Ruggiero I, Piekarska B, Zembala M. 2004 r., Inflamm Res, T. 53(3, str. 100-6.


33. Chemokines and atherosclerosis. Reape T, Groot P. 1999 r., Atherosclerosis, T. 147, str. 213-225.


34. Endogenous CCL2 (monocyte chemotactic protein-1) modulates human immunodeficiency virus type-1 replication and affects cytoskeleton organization in human monocyte-derived macrophages. Fantuzzi L, Spadaro F, Vallanti G, Canini I, Ramoni C, Vicenzi E, Belardelli F, Poli G, Gessani S. 2003 r., Blood., T. 102(7), str. 2334-7.


35. Human monocyte chemoattractant protein-1 (MCP-1). Full-length cDNA cloning, expression in mitogen- stimulated blood mononuclear leukocytes, and sequence similarity to mouse competence gene JE. Yoshimura T, Yuhki N, Moore SK, Appella E, Lerman MI, Leonard. 1989 r., FEBS Lett, T. 244, str. 487-493.


36. Propagermanium reduces atherosclerosis in apolipoprotein E knock-out mice via inhibition of macrophage infiltration. Yamashita, T., Kawashima, S., Ozaki, M., Namiki, M., Inoue, N., Hirata, K., Yokoyama, M. 2002 r., Arterioscler. Thromb. Vasc. Biol., T. 22, str. 969–974.


37. Human vascular smooth muscle cells possess functional CCR5. Schecter A, Calderon T, Berman A, McManus C, Fallon J, Rossikhina M et al. 2000 r., J Biol Chem, T. 275, str. 5466-5471.


38. CCR2-mediated antiinflammatory effects of endothelial tetrahydrobiopterin inhibit vascular injury-induced accelerated atherosclerosis. Ali ZA, Bursill CA, Douglas G, McNeill E, Papaspyridonos M, Tatham AL, Bendall JK, Akhtar AM, Alp NJ, Greaves DR, Channon KM. 2008 r., Circulation, T. 118(14 Suppl), str. S71-7.


39. Novel candidate genes in unstable areas of human atherosclerotic plaques. Papaspyridonos M, Smith A, Burnand KG, Taylor P, Padayachee S, Suckling KE et al. 2006 r., Arterioscler Thromb Vasc Biol, T. 26, str. 1837-1844.


40. PAI-1 in tissue fibrosis. Ghosh AK, Vaughan DE. 2012 r., J Cell Physiol, T. 227(2), str. 493-507.


41. Plasminogen Activator Inhibitor-1 is an Aggregate Response Factor with Pleiotropic Effects on Cell Signaling in Vascular Disease and the Tumor Microenvironment. Church, Mark W. Gramling and Frank C. 2010 r., Thromb Res., T. 125, str. 377-381.


42. Plasminogen activator inhibitor-1 and asthma: role in the pathogenesis and molecular regulation. Ma Z, Paek D, Oh CK. 2009 r., Clin Exp Allergy., T. 39(8), str. 1136-44.


43. Plasminogen activator inhibitor-1 (PAI-1): a key factor linking fibrinolysis and age-related subclinical and clinical conditions. Cesari M, Pahor M, Incalzi RA. 2010 r., Cardiovasc Ther. , T. 28(5), str. 72-91.


44. Endocytic receptor LRP together with tPA and PAI-1 coordinates Mac-1-dependent macrophage migration. Cao C, Lawrence DA, Li Y, Von Arnim CA, Herz J, Su EJ, Makarova A, Hyman BT, Strickland DK, Zhang L. 2006 r., EMBO J., T. 25, str. 1860-1870.


45. Oxidized LDL: diversity, patterns of recognition, and pathophysiology. Levitan I, Volkov S, Subbaiah PV. 2010 r., Antioxid Redox Signal., T. 13(1), str. 39-75.


46. Lipid peroxidation and decomposition--conflicting roles in plaque vulnerability and stability. Parthasarathy S, Litvinov D, Selvarajan K, Garelnabi M. 2008 r., Biochim Biophys Acta, T. 1781(5), str. 221-31.


47. Susceptibility of LDL and its subfractions to glycation. Soran H, Durrington PN. 2011 r., Curr Opin Lipidol., T. 22(4), str. :254-61.


48. Regulation of cholesterol homeostasis in macrophages and consequences for atherosclerotic lesion development. Pennings M, Meurs I, Ye D, Out R, Hoekstra M, Van Berkel TJ, Van Eck M. 2006 r., FEBS Lett., T. 580(23), str. 5588-96.


49. Atherogenic dyslipidemia and oxidative stress: a new look. Rizzo M, Kotur-Stevuljevic J, Berneis K, Spinas G, Rini GB, Jelic-Ivanovic Z, Spasojevic-Kalimanovska V, Vekic J. 2009 r., Transl Res., T. 153(5), str. 217-23.


50. Beyond cholesterol. Modifications of low-density lipoprotein that increase its atherogenicity. Steinberg D, Parthasarathy S, Carew TE, Khoo JC, Witztum JL. 1989 r., N Engl J Med, T. 320(14), str. 915-24.


51. Disease stage-dependent accumulation of lipid and protein oxidation products in human atherosclerosis. Upston JM, Niu X, Brown AJ, Mashima R, Wang H, Senthilmohan R, Kettle AJ, Dean RT, Stocker R. 2002 r., Am J Pathol., T. 160(2), str. 701-10.


52. The oxidative modification hypothesis of atherosclerosis: does it hold for humans? Witztum JL, Steinberg D. 2001 r., Trends Cardiovasc Med., T. 11(3-4), str. 93-102.


53. Aggregation, fusion, and vesicle formation of modified low density lipoprotein particles: molecular mechanisms and effects on matrix interactions. Oörni K, Pentikäinen MO, Ala- Korpela M, Kovanen PT. 2000 r., J Lipid Res., T. 41(11), str. 1703-14.


54. Oxidized low-density lipoprotein and atherosclerosis implications in antioxidant therapy. Mitra S, Deshmukh A, Sachdeva R, Lu J, Mehta JL. 2011 r., Am J Med Sci., T. 342(2), str. 135-42.


55. Monoclonal antibodies against oxidized low-density lipoprotein bind to apoptotic cells and inhibit their phagocytosis by elicited macrophages: evidence that oxidation-specific epitopes mediate macrophage recognition. Chang MK, Bergmark C, Laurila A, Hörkkö S, Han KH, Friedman P, Dennis EA, Witztum JL. 1999 r., Proc Natl Acad Sci U S A., T. 96(11), str. 6353-8.


56. LOX-1, the receptor for oxidized low-density lipoprotein identified from endothelial cells: implications in endothelial dysfunction and atherosclerosis. Chen M, Masaki T, Sawamura T. 2002 r., Pharmacol Ther., T. 95(1), str. 89-100.


57. Isolation of atherogenic modified (desialylated) low density lipoprotein from blood of atherosclerotic patients: separation from native lipoprotein by affinity chromatography. Tertov VV, Sobenin IA, Tonevitsky AG, Orekhov AN, Smirnov VN. 1990 r., Biochem Biophys Res Commun, T. 167:3, str. 1122-7.


58. Multiple-modified desialylated low density lipoproteins that cause intracellular lipid accumulation. Isolation, fractionation and characterization. Tertov VV, Sobenin IA, Gabbasov ZA, Popov EG, Jaakkola O, Solakivi T, Nikkari T, Smirnov VN, Orekhov AN. 1992 r., Lab Invest, T. 67:5, str. 665-75.


59. Lipoprotein aggregation as an essential condition of intracellular lipid accumulation caused by modified low density lipoproteins. Tertov VV, Sobenin IA, Gabbasov ZA, Popov EG, Orekhov AN. 1989 r., Biochem Biophys Res Commun, T. 163:1, str. 489-94.


60. Intracellular cholesterol accumulation is accompanied by enhanced proliferative activity of human aortic intimal cells. Tertov VV, Orekhov AN, Ryong LH, Smirnov VN. 1988 r., Tissue Cell, T. 20:6, str. 849-54.


61. Triggerlike stimulation of cholesterol accumulation and DNA and extracellular matrix synthesis induced by atherogenic serum or low density lipoprotein in cultured cells. Orekhov AN, Tertov VV, Kudryashov SA, Smirnov VN. 1990 r., Circ Res, T. 66:2, str. 311-20.


62. Characterization of desialylated low-density lipoproteins which cause intracellular lipid accumulation. Tertov VV, Sobenin IA, Orekhov AN. 1992 r., Int J Tissue React, T. 14:4, str. 155-62.


63. The macrophage, second edition. Burke B., Lewis CE. 2002 r., Oxford University Press.


64. Phagosome maturation: aging gracefully. Vieira OV, Botelh, RJ, Grinstein S. 2002 r., Biochem J, T. 366, str. 689-704.


65. Receptor-mediated endocytosis: insights from the lipoprotein receptor system. Brown MS, Goldstein JL. 1979 r., Proc Natl Acad Sci U S A, T. 76, str. 3330-3337.


66. Cross-talk between endocytic clearance and secretion in macrophages. Kzhyshkowska J, Krusell L. 2009 r., Immunobiology, T. 214, str. 576-593.


67. The delivery of endocytosed cargo to lysosomes. Luzio JP, Parkinson MD, Gray SR, Bright NA. 2009 r., Biochem Soc Trans, T. 37, str. 1019-1021.


68. Sequestration of aggregated low-density lipoproteins by macrophages. Kruth, H. 2002 r., Curr Opin Lipidol., T. 13(5), str. 483-8.


69. The Macrophage, Second Edition. Burke B, Lewis CE. Oxford : b.n., 2002 r., ed. Oxford University Press.


70. HDL apolipoproteins and ABCA1: partners in the removal of excess cellular cholesterol. Oram, JF. 2003 r., Arterioscler Thromb Vasc Biol., T. 23(5), str. 720-7.


71. ABCA1 and ABCG1 synergize to mediate cholesterol export to apoA-I. Gelissen IC, Harris M, Rye KA, Quinn C, Brown AJ, Kockx M, Cartland S, Packianathan M, Kritharides L, Jessup W. 2006 r., Arterioscler Thromb Vasc Biol., T. 26(3), str. 534-40.


72. ABCG1 has a critical role in mediating cholesterol efflux to HDL and preventing cellular lipid accumulation. Kennedy MA, Barrera GC, Nakamura K, Baldán A, Tarr P, Fishbein MC, Frank J, Francone OL, Edwards PA. 2005 r., Cell Metab., T. 1(2), str. 121-31.


73. Scavenger receptor BI promotes high density lipoprotein-mediated cellular cholesterol efflux. Ji Y, Jian B, Wang N, Sun Y, Moya ML, Phillips MC, Rothblat GH, Swaney JB, Tall AR. 1997 r., J Biol Chem., T. 272(34), str. 20982-5.


74. Cell cholesterol efflux: integration of old and new observations provides new insights. Rothblat GH, de la Llera-Moya M, Atger V, Kellner-Weibel G, Williams DL, Phillips MC. 1999 r., J Lipid Res., T. 40(5), str. 781-96.


75. Atheroprotective reverse cholesterol transport pathway is defective in familial hypercholesterolemia. Bellanger N, Orsoni A, Julia Z, Fournier N, Frisdal E, Duchene E, Bruckert E, Carrie A, Bonnefont-Rousselot D, Pirault J, Saint-Charles F, Chapman MJ, Lesnik P, Le Goff W, Guerin M. 2011 r., Arterioscler Thromb Vasc Biol., T. 31(7), str. 1675- 81.


76. Genome-wide linkage scans for fasting glucose, insulin, and insulin resistance in the National Heart, Lung, and Blood Institute Family Blood Pressure Program: evidence of linkages to chromosome 7q36 and 19q13 from meta-analysis. An P, Freedman BI, Hanis CL, Chen YD, Weder AB, Schork NJ, Boerwinkle E, Province MA, Hsiung CA, Wu X, Quertermous T, Rao DC. 2005 r., Diabetes., T. 54(3), str. 909-14.


77. Variants in the CD36 gene associate with the metabolic syndrome and high-density lipoprotein cholesterol. Love-Gregory L, Sherva R, Sun L, Wasson J, Schappe T, Doria A, Rao DC, Hunt SC, Klein S, Neuman RJ, Permutt MA, Abumrad NA. 2008 r., Hum Mol Genet., T. 17(11), str. 1695-704.


78. Enhanced hepatic apoA-I secretion and peripheral efflux of cholesterol and phospholipid in CD36 null mice. Yue P, Chen Z, Nassir F, Bernal-Mizrachi C, Finck B, Azhar S, Abumrad NA. 2010 r., PLoS One, T. 5(3), str. e9906.


79. CD36-mediated cholesterol efflux is associated with PPARgamma activation via a MAPKdependent COX-2 pathway in macrophages. Bujold K, Rhainds D, Jossart C, Febbraio M, Marleau S, Ong H. 2009 r., Cardiovasc Res., T. 83(3), str. 457-64.


80. Selective role of sterol regulatory element binding protein isoforms in aggregated LDLinduced vascular low density lipoprotein receptor-related protein-1 expression. Costales P, Aledo R, Vérnia S, Das A, Shah VH, Casado M, Badimon L, Llorente-Cortés V. 2010 r., Atherosclerosis, T. 213(2), str. 458-68.


81. Human coronary smooth muscle cells internalize versican-modified LDL through LDL receptor-related protein and LDL receptors. Llorente-Cortés V, Otero-Viñas M, Hurt- Camejo E, Martínez-González J, Badimon L. 2002 r., Arterioscler Thromb Vasc Biol, T. 22(3), str. 387-93.



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