Участие сфинголипидов в патогенезе атеросклероза

Наиболее клинически значимым фактором риска развития сердечно-сосудистых заболеваний (ССЗ) является нарушение липидного обмена. В процессе диагностики ишемической болезни сердца и других ССЗ проводится определение уровня общего холестерина, холестерина липопротеидов низкой и высокой плотности, триглицеридов. Однако в последние годы пристальное внимание уделяется пересечению метаболических путей биосинтеза холестерина и сфинголипидов - группы липидов, в состав которых входит молекула алифатического спирта сфингозина. К ним относятся сфингомиелины, цереброзиды, ганглиозиды и церамиды, сфингозины и сфингозин-1-фосфат (С1Ф). Церамиды и сфингозины обладают проапоптотическими свойствами, а С1Ф защищает клетки от апоптоза. Особое внимание в качестве индуктора ССЗ привлекает церамид. Установлено, что агрегированные липопротеины, изолированные из атеросклеротических зон, обогащены церамидами. Уровень церамида и сфингозина повышается при ишемии/реперфузии сердца, в зоне инфаркта и в крови, а также при гипертонической болезни. С1Ф обладает ярко выраженными кардиопротективными свойствами. Его содержание резко уменьшается при ишемии и инфаркте миокарда. Особую функцию С1Ф выполняет в структуре липопротеидов высокой плотности, являясь одним из главных липидных компонентов этих липопротеидов, что определяет их множественные функции. В последнее время интенсивно ведутся работы по созданию препаратов, способных корректировать метаболизм С1Ф. Наиболее удачными являются препараты, которые в качестве мишени используют рецепторы С1Ф, поскольку все его действия осуществляются через рецепторы. Увеличение содержания церамида и сфингозина и снижение уровня С1Ф в плазме крови может быть важным фактором в развитии атеросклероза. Предлагается использовать определение уровня сфинголипидов в плазме крови для ранней диагностики ишемии сердца и при артериальной гипертонии. В качестве основного метода тестирования этих липидов предполагается использование хромато-масс-спектрометрии.

1. Hinterwirth H, Stegemann C, Mayr M. Lipidomics: Quest for Molecular Lipid Biomarkers in Cardiovascular Disease. Circulation: Cardiovascular Genetics. 2014;7(6):941-54. DOI: 10.1161/CIRCGENETICS.114.000550

2. Fahy E, Subramaniam S, Brown HA, Glass CK, Merrill AH, Murphy RC et al. A comprehensive classification system for lipids. Journal of Lipid Research. 2005;46(5):839-62. DOI: 10.1194/jlr.E400004-JLR200

3. Lydic TA, Goo Y-H. Lipidomics unveils the complexity of the lipi-dome in metabolic diseases. Clinical and Translational Medicine. 2018;7(1):4. DOI: 10.1186/s40169-018-0182-9

4. Hannun YA, Obeid LM. Sphingolipids and their metabolism in physiology and disease. Nature Reviews Molecular Cell Biology. 2017;19(3):175-91. DOI: 10.1038/nrm.2017.107

5. Barenholz Y. Sphingomyelin and cholesterol: from membrane biophysics and rafts to potential medical applications. Sub-Cellular Biochemistry. 2004;37:167-215. PMID: 15376621

6. Stein O, Ben-Naim M, Dabach Y, Hollander G, Stein Y. Modulation of sphingomyelinase-induced cholesterol esterification in fibroblasts, CaCo2 cells, macrophages and smooth muscle cells. Biochimica Et Biophysica Acta. 1992;1126(3):291-7. PMID: 1637857

7. Harmala AS, Porn MI, Slotte JP. Sphingosine inhibits sphingomyelinase-induced cholesteryl ester formation in cultured fibroblasts. Biochimica Et Biophysica Acta. 1993;1210(1):97-104. PMID: 8257725

8. Hannun YA, Obeid LM. Principles of bioactive lipid signalling: lessons from sphingolipids. Nature Reviews Molecular Cell Biology. 2008;9(2):139-50. DOI: 10.1038/nrm2329

9. Mao C. Ceramidases: regulators of cellular responses mediated by ceramide, sphingosine, and sphingosine-1-phosphate. Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids. 2008;1781(9):424-34. DOI: 10.1016/j.bbalip.2008.06.002

10. Grosch S, Alessenko AV, Albi E. The Many Facets of Sphingolipids in the Specific Phases of Acute Inflammatory Response. Mediators of Inflammation. 2018;2018:1-12. DOI: 10.1155/2018/5378284

11. Huitema K, van den Dikkenberg J, Brouwers JFHM, Holthuis JCM. Identification of a family of animal sphingomyelin synthases. The EMBO Journal. 2004;23(1):33-44. DOI: 10.1038/sj.emboj.7600034

12. Maceyka M, Harikumar KB, Milstien S, Spiegel S. Sphingosine-1-phosphate signaling and its role in disease. Trends in Cell Biology. 2012;22(1):50-60. DOI: 10.1016/j.tcb.2011.09.003

13. Maceyka M, Sankala H, Hait NC, Le Stunff H, Liu H, Toman R et al. SphK1 and SphK2, Sphingosine Kinase Isoenzymes with Opposing Functions in Sphingolipid Metabolism. Journal of Biological Chemistry. 2005;280(44):37118-29. DOI: 10.1074/jbc.M502207200

14. Harris CM, Mittelstadt S, Banfor P, Bousquet P, Duignan DB, Gintant G et al. Sphingosine-1-Phosphate (S1P) Lyase Inhibition Causes Increased Cardiac S1P Levels and Bradycardia in Rats. Journal of Pharmacology and Experimental Therapeutics. 2016;359(1):151-8. DOI: 10.1124/jpet.116.235002

15. Dong J, Liu J, Lou B, Li Z, Ye X, Wu M et al. Adenovirus-mediated overexpression of sphingomyelin synthases 1 and 2 increases the atherogenic potential in mice. Journal of Lipid Research. 2006;47(6):1307-14. DOI: 10.1194/jlr.M600040-JLR200

16. Wang S, Zhou L, Wang Z, Shi X, Xu G. Simultaneous metabolo-mics and lipidomics analysis based on novel heart-cutting twodimensional liquid chromatography-mass spectrometry. Analytica Chimica Acta. 2017;966:34-40. DOI: 10.1016/j.aca.2017.03.004

17. Ellims AH, Wong G, Weir JM, Lew P, Meikle PJ, Taylor AJ. Plasma lipidomic analysis predicts non-calcified coronary artery plaque in asymptomatic patients at intermediate risk of coronary artery disease. European Heart Journal - Cardiovascular Imaging. 2014;15(8):908-16. DOI: 10.1093/ehjci/jeu033

18. Tham YK, Huynh K, Mellett NA, Henstridge DC, Kiriazis H, Ooi JYY et al. Distinct lipidomic profiles in models of physiological and pathological cardiac remodeling, and potential therapeutic strategies. Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids. 2018;1863(3):219-34. DOI: 10.1016/j.bbalip.2017.12.003

19. Haus JM, Kashyap SR, Kasumov T, Zhang R, Kelly KR, DeFronzo ^A et al. Plasma Ceramides Are Elevated in Obese Subjects With Type 2 Diabetes and Correlate With the Severity of Insulin Resistance. Diabetes. 2009;58(2):337-43. DOI: 10.2337/db08-1228

20. Лебедев А.Т. Масс-спектрометрия в органической химии. М.: Техносфера, 2015. -704с. ISBN 978-5-94836-409-4

21. Merrill Jr. AH, Sullards MC, Allegood JC, Kelly S, Wang E. Sphingolipidomics: High-throughput, structure-specific, and quantitative analysis of sphingolipids by liquid chromatography tandem mass spectrometry. Methods. 2005;36(2):207-24. DOI: 10.1016/j.ymeth.2005.01.009

22. Zheng W, Kollmeyer J, Symolon H, Momin A, Munter E, Wang E et al. Ceramides and other bioactive sphingolipid backbones in health and disease: Lipidomic analysis, metabolism and roles in membrane structure, dynamics, signaling and autoph-agy. Biochimica et Biophysica Acta (BBA) - Biomembranes. 2006;1758(12):1864-84. DOI: 10.1016/j.bbamem.2006.08.009

23. Gulati S, Liu Y, Munkacsi AB, Wilcox L, Sturley SL. Sterols and sphingolipids: Dynamic duo or partners in crime? Progress in Lipid Research. 2010;49(4):353-65. DOI: 10.1016/j.plip-res.2010.03.003

24. Jin S, Zhou F, Katirai F, Li P-L. Lipid Raft Redox Signaling: Molecular Mechanisms in Health and Disease. Antioxidants & Redox Signaling. 2011;15(4):1043-83. DOI: 10.1089/ars.2010.3619

25. Megha, London E. Ceramide Selectively Displaces Cholesterol from Ordered Lipid Domains (Rafts): implications for lipid raft structure and function. Journal of Biological Chemistry. 2004;279(11):9997-10004. DOI: 10.1074/jbc.M309992200

26. Slotte JP, Bierman EL. Depletion of plasma-membrane sphingomyelin rapidly alters the distribution of cholesterol between plasma membranes and intracellular cholesterol pools in cultured fibroblasts. Biochemical Journal. 1988;250(3):653-8. DOI: 10.1042/bj2500653

27. Marmillot P, Patel S, Lakshman MR. Reverse cholesterol transport is regulated by varying fatty acyl chain saturation and sphingomyelin content in reconstituted high-density lipoproteins. Metabolism. 2007;56(2):251-9. DOI: 10.1016/j.metabol.2006.09.021

28. Subbaiah PV, Gesquiere LR, Wang K. Regulation of the selective uptake of cholesteryl esters from high density lipoproteins by sphingomyelin. Journal of Lipid Research. 2005;46(12):2699-705. DOI: 10.1194/jlr.M500263-JLR200

29. Hannun YA. Functions of Ceramide in Coordinating Cellular Responses to Stress. Science. 1996;274(5294):1855-9. DOI: 10.1126/science.274.5294.1855

30. Bismuth J, Lin P, Yao Q, Chen C. Ceramide: A common pathway for atherosclerosis? Atherosclerosis. 2008;196(2):497-504. DOI: 10.1016/j.atherosclerosis.2007.09.018

31. Kalliolias GD, Ivashkiv LB. TNF biology, pathogenic mechanisms and emerging therapeutic strategies. Nature Reviews Rheumatology. 2016;12(1):49-62. DOI: 10.1038/nrrheum.2015.169

32. Bayley J-P, Ottenhoff THM, Verweij CL. Is there a future for TNF promoter polymorphisms? Genes & Immunity. 2004;5(5):315-29. DOI: 10.1038/sj.gene.6364055

33. Герасимова О.Н., Сигалович Е.Ю., Данковцева Е.Н., Наконечников С.Н., Никитин А.Г., Иванова З.В. и др. Связь носительства аллеля A полиморфного маркера G(-238) A генаTNF-a с неблагоприятным прогнозом у больных с хронической систолической сердечной недостаточностью. Кардиология. 2015;55(9):25-30

34. Majumdar I, Mastrandrea LD. Serum sphingolipids and inflammatory mediators in adolescents at risk for metabolic syndrome. Endocrine. 2012;4l(3):442-9. DOI: 10.1007/s12020-011-9589-4

35. Fu P, Ebenezer DL, Ha AW, Suryadevara V, Harijith A, Natarajan V. Nuclear lipid mediators: Role of nuclear sphingolipids and sphin-gosine-1-phosphate signaling in epigenetic regulation of inflammation and gene expression. Journal of Cellular Biochemistry. 2018;119(8):6337-53. DOI: 10.1002/jcb.26707

36. Wang Y, Park N-Y, Jang Y, Ma A, Jiang Q. Vitamin E y-Tocotrienol Inhibits Cytokine-Stimulated NF-kB Activation by Induction of Anti-Inflammatory A20 via Stress Adaptive Response Due to Modulation of Sphingolipids. The Journal of Immunology. 2015;195(1):126-33. DOI: 10.4049/jimmunol.1403149

37. Chiricozzi E, Loberto N, Schiumarini D, Samarani M, Mancini G, Tamanini A et al. Sphingolipids role in the regulation of inflammatory response: From leukocyte biology to bacterial infection. Journal of Leukocyte Biology. 2018;103(3):445-56. DOI: 10.1002/JLB.3MR0717-269R

38. Espaillat MP, Kew RR, Obeid LM. Sphingolipids in neutrophil function and inflammatory responses: Mechanisms and implications for intestinal immunity and inflammation in ulcerative colitis. Advances in Biological Regulation. 2017;63:140-55. DOI: 10.1016/j.jbior.2016.11.001

39. Kulkarni H, Meikle PJ, Mamtani M, Weir JM, Barlow CK, Jowett JB et al. Plasma Lipidomic Profile Signature of Hypertension in Mexican American Families: Specific Role of Diacylglycerols. Hypertension. 2013;62(3):621-6. DOI: 10.1161/HYPERTENSIONAHA.113.01396

40. Spijkers LJA, van den Akker RFP, Janssen BJA, Debets JJ, De Mey JGR, Stroes ESG et al. Hypertension Is Associated with Marked Alterations in Sphingolipid Biology: A Potential Role for Ceramide. PLoS ONE. 2011;6(7):e21817. DOI: 10.1371/journal.pone.0021817

41. Spijkers LJA,Janssen BJA, NelissenJ, Meens MJPMT, Wijesinghe D, Chalfant CE et al. Antihypertensive Treatment Differentially Affects Vascular Sphingolipid Biology in Spontaneously Hypertensive Rats. PLoS ONE. 2011;6(12):e29222. DOI: 10.1371/journal.pone.0029222

42. Fenger M, Linneberg A, Jorgensen T, Madsbad S, Sobye K, Eugen-Olsen J et al. Genetics of the ceramide/sphingosine-1-phosphate rheostat in blood pressure regulation and hypertension. BMC Genetics. 2011;12(1):44. DOI: 10.1186/1471-2156-12-44

43. Borodzicz S, Czarzasta K, Kuch M, Cudnoch-Jedrzejewska A. Sphingolipids in cardiovascular diseases and metabolic disorders. Lipids in Health and Disease. 2015;14(1):55. DOI: 10.1186/s12944-015-0053-y

44. Igarashi J, Michel T. Sphingosine-1-phosphate and modulation of vascular tone. Cardiovascular Research. 2009;82(2):212-20. DOI: 10.1093/cvr/cvp064

45. Tong X, Peng H, Liu D, Ji L, Niu C, Ren J et al. High-density lipoprotein of patients with Type 2 Diabetes Mellitus upregulates cyclo-oxgenase-2 expression and prostacyclin I-2 release in endothelial cells: relationship with HDL-associated sphingosine-1-phosphate. Cardiovascular Diabetology. 2013;12(1):27. DOI: 10.1186/1475-2840-12-27

46. Zhou J-W, Tsui SKW, Ng MCY, Geng H, Li S-K, So W-Y et al. Apolipoprotein M Gene (APOM) Polymorphism Modifies Metabolic and Disease Traits in Type 2 Diabetes. PLoS ONE. 2011;6(2):e17324. DOI: 10.1371/journal.pone.0017324

47. Bhat OM, Yuan X, Li G, Lee R, Li P-L. Sphingolipids and Redox Signaling in Renal Regulation and Chronic Kidney Diseases. Antioxidants & Redox Signaling. 2018;28(10):1008-26. DOI: 10.1089/ars.2017.7129

48. Bellis C, Kulkarni H, Mamtani M, Kent JW, Wong G, Weir JM et al. Human Plasma Lipidome Is Pleiotropically Associated With Cardiovascular Risk Factors and Death. Circulation: Cardiovascular Genetics. 2014;7(6):854-63. DOI: 10.1161/CIRCGENETICS.114.000600

49. Draisma HH, Reijmers TH, Meulman JJ, van der Greef J, Hankemeier T, Boomsma DI. Hierarchical clustering analysis of blood plasma lipidomics profiles from mono- and dizygotic twin families. European Journal of Human Genetics. 2013;21(1):95-101. DOI: 10.1038/ejhg.2012.110

50. Maziere JC, Maziere C, Mora L, Polonovski J. Impairment of exogenous sphingomyelin degradation in cultured fibroblasts from familial hypercholesterolemia. FEBS letters. 1984;173(1):159-63. PMID: 6745424

51. Bellanger N, Orsoni A, Julia Z, Fournier N, Frisdal E, Duchene E et al. Atheroprotective Reverse Cholesterol Transport Pathway Is Defective in Familial Hypercholesterolemia. Arteriosclerosis, Thrombosis, and Vascular Biology. 2011;31(7):1675-81. DOI: 10.1161/ATVBAHA.111.227181

52. Versmissen J, Vongpromek R, Yahya R, van der Net JB, van Vark-van der Zee L, Blommesteijn-Touw J et al. Familial hypercholester-olaemia: cholesterol efflux and coronary disease. European Journal of Clinical Investigation. 2016;46(7):643-50. DOI: 10.1111/eci.12643

53. Pan W, Yu J, Shi R, Yan L, Yang T, Li Y et al. Elevation of ceramide and activation of secretory acid sphingomyelinase in patients with acute coronary syndromes: Coronary Artery Disease. 2014;25(3):1. DOI: 10.1097/MCA.0000000000000079

54. Baranowski M, Gorski J. Heart sphingolipids in health and disease. Advances in Experimental Medicine and Biology. 2011;721:41-56. DOI: 10.1007/978-1-4614-0650-1_3

55. Bojic L, McLaren D, Shah V, Previs S, Johns D, Castro-Perez J. Lipidome of Atherosclerotic Plaques from Hypercholesterolemic Rabbits. International Journal of Molecular Sciences. 2014;15(12):23283-93. DOI: 10.3390/ijms151223283

56. Czarny M, Schnitzer JE. Neutral sphingomyelinase inhibitor scy-phostatin prevents and ceramide mimics mechanotransduction in vascular endothelium. American Journal of Physiology-Heart and Circulatory Physiology. 2004;287(3):H1344-52. DOI: 10.1152/ajpheart.00222.2004

57. Park T-S, Goldberg IJ. Sphingolipids, Lipotoxic Cardiomyopathy, and Cardiac Failure. Heart Failure Clinics. 2012;8(4):633-41. DOI: 10.1016/j.hfc.2012.06.003

58. Zhang DX, Fryer RM, Hsu AK, Zou AP, Gross GJ, Campbell WB et al. Production and metabolism of ceramide in normal and isch-emic-reperfused myocardium of rats. Basic Research in Cardiology. 2001;96(3):267-74. PMID: 11403420

59. Baranowski M, Zabielski P, Blachnio A, Gorski J. Effect of exercise duration on ceramide metabolism in the rat heart. Acta Physiologica. 2008;192(4):519-29. DOI: 10.1111/j.1748-1716.2007.01755.x

60. Knapp M, Zendzian-Piotrowska M, Blachnio-Zabielska A, Zabielski P, Kurek K, Gorski J. Myocardial infarction differentially alters sphingolipid levels in plasma, erythrocytes and platelets of the rat. Basic Research in Cardiology. 2012;107(6):294. DOI: 10.1007/s00395-012-0294-0

61. Knapp M, Lisowska A, Zabielski P, Musial W, Baranowski M. Sustained decrease in plasma sphingosine-1-phosphate concentration and its accumulation in blood cells in acute myocardial infarction. Prostaglandins & Other Lipid Mediators. 2013;106:53-61. DOI: 10.1016/j.prostaglandins.2013.10.001

62. Egom EE, Mamas MA, Chacko S, Stringer SE, Charlton-Menys V, El-Omar M et al. Serum sphingolipids level as a novel potential marker for early detection of human myocardial ischaemic injury. Frontiers in Physiology. 2013;4:130. DOI: 10.3389/fphys.2013.00130

63. Song Y, Hou M, Li Z, Luo C, Ou J-S, Yu H et al. TLR4/NF-kB/ Ceramide signaling contributes to Ox-LDL-induced calcification of human vascular smooth muscle cells. European Journal of Pharmacology. 2017;794:45-51. DOI: 10.1016/j.ejphar.2016.11.029

64. Singh RK, Haka AS, Brumfield A, Grosheva I, Bhardwaj P, Chin HF et al. Ceramide activation of RhoA/Rho kinase impairs actin polymerization during aggregated LDL catabolism. Journal of Lipid Research. 2017;58(10):1977-87. DOI: 10.1194/jlr.M076398

65. Kurano M, Yatomi Y. Sphingosine 1-Phosphate and Atherosclerosis. Journal of Atherosclerosis and Thrombosis. 2018;25(l):16-26. DOI: 10.5551/jat.RV17010

66. Sattler K, Levkau B. Sphingosine-1-phosphate as a mediator of high-density lipoprotein effects in cardiovascular protection. Cardiovascular Research. 2008;82(2):201-11. DOI: 10.1093/cvr/cvp070

67. Christoffersen C, Obinata H, Kumaraswamy SB, Galvani S, Ahnstrom J, Sevvana M et al. Endothelium-protective sphin-gosine-1-phosphate provided by HDL-associated apolipo-protein M. Proceedings of the National Academy of Sciences. 2011;108(23):9613-8. DOI: 10.1073/pnas.1103187108

68. Persegol L, Darabi M, Dauteuille C, Lhomme M, Chantepie S, Rye K-A et al. Small dense HDLs display potent vasorelaxing activity, reflecting their elevated content of sphingosine-1-phosphate. Journal of Lipid Research. 2018;59(l):25-34. DOI: 10.1194/jlr.M076927

69. Pappu R, Schwab SR, Cornelissen I, Pereira JP, Regard JB, Xu Y et al. Promotion of Lymphocyte Egress into Blood and Lymph by Distinct Sources of Sphingosine-1-Phosphate. Science. 2007;316(5822):295-8. DOI: 10.1126/science.1139221

70. Knapp M, Baranowski M, Czarnowski D, Lisowska A, Zabielski P, Gorski J et al. Plasma sphingosine-1-phosphate concentration is reduced in patients with myocardial infarction. Medical Science Monitor: International Medical Journal of Experimental and Clinical Research. 2009;15(9):CR490-493. PMID: 19721401

71. Hillis GS, Flapan AD. Cell adhesion molecules in cardiovascular disease: a clinical perspective. Heart. 1998;79(5):429-31. DOI: 10.1136/hrt.79.5.429

72. Peters S, Alewijnse A. Sphingosine-1-phosphate signaling in the cardiovascular system. Current Opinion in Pharmacology. 2007;7(2):186-92. DOI: 10.1016/j.coph.2006.09.008

73. Ryo Terao, Megumi Honjo, Makoto Aihara. Apolipoprotein M Inhibits Angiogenic and Inflammatory Response by Sphingosine 1-Phosphate on Retinal Pigment Epithelium Cells. International Journal of Molecular Sciences. 2017;19(1):112. DOI: 10.3390/ijms19010112

74. Sattler K, Lehmann I, Graler M, Brocker-Preuss M, Erbel R, Heusch G et al. HDL-Bound Sphingosine 1-Phosphate (S1P) Predicts the Severity of Coronary Artery Atherosclerosis. Cellular Physiology and Biochemistry. 2014;34(1):172-84. DOI: 10.1159/000362993

75. Orsoni A, Therond P, Tan R, Giral P, Robillard P, Kontush A et al. Statin action enriches HDL3 in polyunsaturated phospholipids and plasmalogens and reduces LDL-derived phospholipid hydroperoxides in atherogenic mixed dyslipidemia. Journal of Lipid Research. 2016;57(11):2073-87. DOI: 10.1194/jlr.P068585

76. Meikle PJ, Wong G, Tan R, Giral P, Robillard P, Orsoni A et al. Statin action favors normalization of the plasma lipidome in the atherogenic mixed dyslipidemia of MetS: potential relevance to statin-associated dysglycemia. Journal of Lipid Research. 2015;56(12):2381-92. DOI: 10.1194/jlr.P061143