Role of lipid metabolism and systemic inflammation in the development of atherosclerosis in animal models

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Systemic inflammation makes a significant contribution to the pathogenesis of atherosclerosis and has been the subject of numerous studies. Works aiming to analyze the mechanisms of atherosclerosis development often include experiments on animals. A primary task of such research is the characterization, justification, and selection of an adequate model.

Aim. To evaluate the peculiarities of lipid metabolism and systemic inflammation in chronic obstructive pulmonary disease (COPD) in the development of atherosclerosis in animal models.

Materials and Methods. Analyses of cross-links between species-specific peculiarities of lipid metabolism and the immune response, as well as a bioinformatic analysis of differences in Toll-like receptor 4 (TLR4) in mice, rats, and rabbits in comparison with its human homolog, were carried out. A search for and analysis of the amino acid sequences of human, mouse, rat, and rabbit TLR4 was performed in the International database GenBank of National Center of Biotechnical Information and in The Universal Protein Resource (UniProt) database. Multiple alignments of the TLR4 amino acid sequences were implemented in the Clustal Omega program, version 1.2.4. Reconstruction and visualization of molecular phylogenetic trees were performed using the MEGA7 program according to the Neighbor-Joining and Maximum Parsimony methods.

Results. Species-specific differences of the peculiarities of lipid metabolism and the innate immune response in humans, mice, and rabbits were shown that must be taken into account in analyses of study results.

Conclusion.Disorders in lipid metabolism and systemic inflammation mediated by the innate immune system participating in the pathogenesis of atherosclerosis in COPD possess species-specific differences that should be taken into account in analyses of study results.

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Stanislav N. Kotlyarov

Ryazan State Medical University

Author for correspondence.
ORCID iD: 0000-0002-7083-2692
SPIN-code: 3341-9391
ResearcherId: Q-3633-2017

MD, PhD, Head of the Nurse Department

Russian Federation, Ryazan, Russia

Anna A. Kotlyarova

Ryazan State Medical University

SPIN-code: 9353-0139
ResearcherId: K-7882-2018

PhD in Biological Sciences, Assistant of the Department of Pharmacology with the Course of Pharmacy of the Faculty of Additional Professional Education

Russian Federation, Ryazan, Russia


  1. Kalinin RE, Suchkov IA, Chobanyan AA. Prospects for forecasting the course of obliterating atherosclerosis of lower limb arteries. Science of the young (Eruditio Juvenium). 2019;7(2):274-82. (In Russ). doi: 10.23888/HMJ201972274-282
  2. Schroder K, Irvine KM, Taylor MS, et al. Conservation and divergence in toll-like receptor 4-regulated gene expression in primary human versus mouse macrophages. Proceeding of the National Acade-my of Sciences of the United States of America. 2012; 109(16):E944-53. doi: 10.1073/pnas.1110156109
  3. Vaure C, Liu Y. A comparative review of toll-like receptor 4 expression and functionality in different animal species. Frontiers in Immunology. 2014;5: 316. doi: 10.3389/fimmu.2014.00316
  4. Bagheri M, Zahmatkesh A. Evolution and species-specific conservation of toll-like receptors in terrestrial vertebrates. International Reviews of Immunology. 2018;37(5):217-28. doi: 10.1080/08830185. 2018.1506780
  5. Liu G, Zhang H, Zhao C, et al. Evolutionary History of the Toll-Like Receptor Gene Family across Vertebrates. Genome Biology and Evolution. 2020;12(1):3615-34. doi: 10.1093/gbe/evz266
  6. Kajikawa O, Frevert CW, Lin S-M, et al. Gene ex-pression of toll-like receptor-2, toll-like receptor-4, and MD2 is differentially regulated in rabbits with Escherichia coli pneumonia. Gene. 2005;344:193-202. doi: 10.1016/j.gene.2004.09.032
  7. Hajjar AM, Ernst RK, Tsai JH, et al. Human toll-like receptor 4 recognizes host-specific LPS modifications. Nature Immunology. 2002;3(4):354-91. doi: 10.1038/ni777
  8. Vasl J, Oblak A, Gioannini TL, et al. Novel roles of lysines 122, 125, and 58 in functional differences between human and murine MD-2. Journal of Immunology. 2009;183(8):5138-45. doi:10.4049/j immunol.0901544
  9. Dusuel A, Deckert V, Pais DE Barros J-P, et al. Hu-man CETP lacks lipopolysaccharide transfer activity, but worsens inflammation and sepsis outcomes in mice. Journal of Lipid Research. 2021; 62:100011. doi: 10.1194/jlr.RA120000704
  10. Tall AR, Yvan-Charvet L. Cholesterol, inflammation and innate immunity. Nature Reviews Immunology. 2015;15:104-16. doi: 10.1038/nri3793
  11. Niimi M, Chen Y, Yan H, et al. Hyperlipidemic Rabbit Models for Anti-Atherosclerotic Drug Development. Applied Sciences. 2020;10:8681. doi: 10.3390/app10238681
  12. Shrestha S, Wu BJ, Guiney L, et al. Cholesteryl ester transfer protein and its inhibitors. Journal of Lipid Research. 2018;59(5):772-83. doi: 10.1194/jlr.R082735
  13. Azzam KM, Fessler MB. Crosstalk between reverse cholesterol transport and innate immunity. Trends in Endocrinology and Metabolism: TEM. 2012;23 (4):169-78. doi: 10.1016/j.tem. 2012.02.001
  14. Venancio TM, Machado RM, Castoldi A, et al. CETP Lowers TLR4 Expression Which Attenuates the Inflammatory Response Induced by LPS and Polymicrobial Sepsis. Mediators of Inflammation. 2016;2016:1784014. doi: 10.1155/2016/1784014
  15. Blauw LL, Wang Y, van Dijk KW, et al. A Novel Role for CETP as Immunological Gatekeeper: Raising HDL to Cure Sepsis? Trends in Endocri-nology & Metabolism. 2020;31(5):334-43. doi:10.1016/j. tem.2020.01.003
  16. Zhang J, Niimi M, Yang D, et al. Deficiency of Cholesteryl Ester Transfer Protein Protects Against Atherosclerosis in Rabbits. Arteriosclerosis, Thrombosis, and Vascular Biology. 2017;37(6):1068-75. doi: 10.1161/ATVBAHA.117.309114
  17. Grion CMC, Cardoso LTQ, Perazolo TF, et al. Lipoproteins and CETP levels as risk factors for severe sepsis in hospitalized patients. European Journal of Clinical Investigation. 2010;40(4):330-8. doi: 10.1111/j.1365-2362.2010.02269.x
  18. Ciesielska A, Matyjek M, Kwiatkowska K. TLR4 and CD14 trafficking and its influence on LPS-induced proinflammatory signaling. Cellular and Molecular Life Sciences. 2020. doi: 10.1007/s000 18-020-03656-y
  19. Minniti ME, Pedrelli M, Vedin L‐L, et al. Insights From Liver‐Humanized Mice on Cholesterol Lipoprotein Metabolism and LXR‐Agonist Pharmacodynamics in Humans. Hepatology. 2020;72(2): 656-70. doi: 10.1002/hep.31052
  20. Shrestha S, Wu BJ, Guiney L, et al. Cholesteryl ester transfer protein and its inhibitors. Journal of Lipid Research. 2018;59(5):772-83. doi: 10.1194/jlr.R082735
  21. Dixit SM, Ahsan M, Senapati S. Steering the Lipid Transfer To Unravel the Mechanism of Cholesteryl Ester Transfer Protein Inhibition. Biochemistry. 2019; 58(36):3789-801. doi: 10.1021/acs.biochem.9b00301
  22. Trinder M, Genga KR, Kong HJ, et al. Cholesteryl Ester Transfer Protein Influences High-Density Lipoprotein Levels and Survival in Sepsis. American Journal of Respiratory and Critical Care Medicine. 2019; 199(7):854-62. doi: 10.1164/rccm.201806-1157OC
  23. Topchiy E, Cirstea M, Kong HJ, et al. Lipopolysaccharide Is Cleared from the Circulation by Hepatocytes via the Low Density Lipoprotein Receptor. PLoS One. 2016;11(5):e0155030. doi:10.1371/ journal.pone.0155030
  24. Munford RS, Weiss JP, Lu M. Biochemical transformation of bacterial lipopolysaccharides by acyloxyacyl hydrolase reduces host injury and promotes recovery. Journal of Biological Chemistry. 2020; 295(51):17842-51. doi: 10.1074/jbc.REV120.015254
  25. Schwartz GG, Olsson AG, Abt M, et al. Effects of dalcetrapib in patients with a recent acute coronary syndrome. The New England Journal of Medicine. 2012;367(22):2089-99. doi: 10.1056/NEJMoa1206797
  26. Quintão ECR. The controversy over the use of cholesteryl ester transfer protein inhibitors: is there some light at the end of the tunnel? European Journal of Clinical Investigation. 2016;46(6):581-9. doi: 10.1111/eci.12626
  27. Gautier T, Klein A, Deckert V, et al. Effect of plasma phospholipid transfer protein deficiency on lethal endotoxemia in mice. Journal of Biological Chemistry. 2008;283(27):18702-10. doi:10.1074/ jbc.M802802200
  28. Poznyak AV, Silaeva, YY, Orekhov AN, et al. Animal models of human atherosclerosis: current progress. Brazilian Journal of Medical and Biological Research. 2020;53(6):e9557. doi: 10.1590/1414-431 x20209557
  29. Morehouse LA, Sugarman ED, Bourassa P-A, et al. Inhibition of CETP activity by torcetrapib reduces susceptibility to diet-induced atherosclerosis in New Zealand White rabbits. Journal of Lipid Research. 2007;48(6):1263-72. doi: 10.1194/jlr.M600 332-JLR200
  30. Fan J, Chen Y, Yan H, et al. Principles and Applications of Rabbit Models for Atherosclerosis Research. Journal of Atherosclerosis and Thrombosis. 2018;25(3):213-20. doi: 10.5551/jat.RV17018
  31. Fan J, Kitajima S, Watanabe T, et al. Rabbit models for the study of human atherosclerosis: from pathophysiological mechanisms to translational medicine. Pharmacology & Therapeutics. 2015. Vol. 146. P. 104-19. doi: 10.1016/j.pharmthera.2014.09.009
  32. Koike T, Kitajima S, Yu Y, et al. Expression of human apoAII in transgenic rabbits leads to dyslipidemia: a new model for combined hyperlipidemia. Arteriosclerosis, Thrombosis, and Vascular Biology. 2009;29(12):2047-53. doi: 10.1161/ATVBAHA.109. 190264
  33. Liu J-Q, Li W-X, Zheng J-J, et al. Gain and loss events in the evolution of the apolipoprotein family in vertebrata. BMC Evolutionary Biology. 2019;19 (1):209. doi: 10.1186/s12862-019-1519-8
  34. Blanco-Vaca F, Escolà-Gil CJ, Martín-Campos JM, et al. Role of apoA-II in lipid metabolism and atherosclerosis: advances in the study of an enigmatic protein. Journal of Lipid Research. 2001;42(11):1727-39.
  35. Koike T, Koike Y, Yang D, et al. Human apolipoprotein A-II reduces atherosclerosis in knock-in rabbits. Atherosclerosis. 2021;316:32-40. doi:10.1016/ j.atherosclerosis.2020.11.028
  36. Escolà-Gil JC, Marzal-Casacuberta À, Julve-Gil J, et al. Human apolipoprotein A-II is a proatherogenic molecule when it is expressed in trans-genic mice at a level similar to that in humans: evidence of a potentially relevant species-specific interaction with diet. Journal of Lipid Research. 1998;39(2):457-62.
  37. Wang Y, Niimi M, Nishijima K, et al. Human apolipoprotein A-II protects against diet-induced atherosclerosis in transgenic rabbits. Arteriosclerosis, Thrombosis, and Vascular Biology. 2013;33(2): 224-31. doi: 10.1161/ATVBAHA.112.300445
  38. Niimi M, Chen Y, Yan H, et al. Hyperlipidemic Rabbit Models for Anti-Atherosclerotic Drug De-velopment. Applied Sciences. 2020;10(23):8681. doi: 10.3390/app10238681
  39. Chiesa G, Hobbs HH, Koschinsky ML, et al. Reconstitution of Lipoprotein(a) by Infusion of Human Low Density Lipoprotein into Transgenic Mice Expressing Human Apolipoprotein(a). The Journal of Biological Chemistry. 1992;267(34): 24369-74.
  40. Fan JL, Shimoyamada H, Hj S, et al. Transgenic Rabbits Expressing Human Apolipoprotein(a) Develop More Extensive Atherosclerotic Lesions in Response to a CholesterolRich Diet. Arteriosclerosis, Thrombosis, and Vascular Biology. 2001;21 (1):88-94. doi: 10.1161/01.ATV.21.1.88
  41. Takahashi S, Ito T, Zenimaru Y, et al. Species differences of macrophage very low-density-lipoprotein (VLDL) receptor protein expression. Biochemical and Biophysical Research Communications. 2011; 407(4):656-62. doi: 10.1016/j.bbrc.2011.03.069
  42. Muijsers RB, ten Hacken NH, van Ark I, et al. L-Arginine is not the limiting factor for nitric oxide synthesis by human alveolar macrophages in vitro. European Respiratory Journal. 2001;18(4):667-71. doi: 10.1183/09031936.01.00101301
  43. Schneemann M, Schoedon G. Species differences in macrophage NO production are important. Na-ture Immunology. 2002;3(2):102. doi: 10.1038/ni 0202-102a

Supplementary files

Supplementary Files
1. Fig. 1. Alignment of amino acid sequences of human, mouse, rat, and rabbit TLR4 (TIR domain-containing protein). Implemented in the CLUSTAL O program, version 1.2.4. The table of identity of amino acid sequences was constructed using the BLAST® tool (Basic Local Alignment Search Tool)

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2. Fig. 2. Phylogenetic tree of TLR4 of humans, mice, rats, and rabbits (protein-containing TIR-domain) constructed using the Neighbor-Joining method

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Copyright (c) 2021 Kotlyarov S., Kotlyarova A.A.

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