Chapter 1. Literature Review
1. Hypotheses and theories of the pathogenesis of atherosclerosis
1.1. Cholesterol theory of atherosclerosis
1.2. Oxidative modification hypothesis
1.3. Infectious and autoimmune inflammation as a cause of atherosclerosis development
1.4. Epicardial and perivascular fat as a cause of atherosclerosis development
2. Experimental models of atherosclerosis
2.1. Hypercholesterol diet as a method of inducing atherosclerosis in experimental animals
2.2. Genetic models of atherosclerosis
2.3. Infectious models of atherosclerosis
2.4. Autoimmune models of atherosclerosis
Chapter 2. Organization and methods of research
2.1. Organization of research
2.2. Materials and research methods
Chapter 3. Research results
3.1. Development of a scheme for immunization of rats with native human LDL, inducing a hyperimmune response against nLDL
3.2. Kinetics of antibodies against native human LDL and autoantibodies against LDL in rats immunized with native human LDL
3.3. Serum cholesterol fractions and lipid composition
adrenal glands of rats immunized with native human LDL
3.3.1. Low and high density lipoprotein cholesterol in rats,
immunized with human nLDL
3.3.2. Lipid composition of the adrenal glands of rats immunized with nLDL
person
3.4. Morphological and histological analysis of the heart and aortic arch in
rats immunized with native human LDL
3.4.1. Changes in the wall of the aortic arch in rats immunized with nLDL
person
3.4.2.Epicardial and perivascular fat in rats,
immunized with native human LDL
Chapter 4. Discussion of results
4.1. Analysis of the adequacy of the experimental model of rat atherosclerosis caused by immunization with native human LDL to human atherosclerosis
4.2. A model of atherosclerosis induced by immunization with native LDL as evidence of the hypothesis that an autoimmune reaction against native LDL is the cause of the development of dyslipoproteinemia and
atherosclerosis
Literature
LIST OF ABBREVIATIONS
DHEA - dehydroepiandrosterone
IHD - coronary heart disease
NIDDM - non-insulin dependent diabetes mellitus
ELISA - enzyme immunoassay
HDL - high density lipoproteins
LDL - low density lipoproteins
NAF - Freund's incomplete adjuvant
nLDL - native low-density lipoproteins
PAF - Freund's complete adjuvant
CVD - cardiovascular diseases
PAT - perivascular adipose tissue
FR - saline solution
CS - cholesterol
EAT - epicardial adipose tissue
ApoE-/-mice - apolipoprotein E-deficient mice
1LEK-/-mice - mice with a deficiency of receptors for low-density lipoproteins
Recommended list of dissertations
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Introduction of the dissertation (part of the abstract) on the topic “Experimental model of atherosclerosis in rats caused by immunization with native human low-density lipoproteins”
Introduction
Relevance of the study
Atherosclerosis underlies a wide range of cardiovascular diseases. Despite numerous studies, the etiology and pathogenesis of this disease remain unknown. Elucidating the mechanisms of induction and development of atherosclerosis in humans is difficult due to the long-term preclinical stage of atherosclerosis development and the lack of non-invasive forms of its detection. As a result, most studies in humans are carried out after the onset of clinical signs of the disease, when it is already well advanced. Experimental models allow us to study the causes of atherosclerosis and its early, preclinical stages. In addition, the possibility of inducing atherosclerosis in experimental animals using any influence is an effective way to test the role of certain factors in initiating the development of atherosclerosis.
Many external and internal factors leading to atherosclerosis are discussed. Among them are excess cholesterol intake, autoimmune reactions, inflammation, and defects in lipoprotein receptor genes. Experimental atherosclerosis is caused mainly by a hypercholesterol diet and genetic manipulations leading to disruption of lipoprotein metabolism. However, existing experimental models do not fully reproduce the typical human clinical stages and signs of atherosclerosis development. Despite numerous studies conducted on these experimental models, it has not yet been possible to identify the leading etiological factors of atherosclerosis or prove that they are the factors that cause the disease in experimental animals. One of the most attractive hypotheses today about the causes of the development of atherosclerosis is the hypothesis according to which the oxidation of low-density lipoproteins (LDL) leads to their modification and the development of an autoimmune reaction to them.
The autoimmune reaction within the framework of this hypothesis is considered either as the leading etiological factor of the disease, or as one of the main pathogenetic links. However, the data available today on the level of autoantibodies to oxidized LDL in patients with atherosclerosis and healthy people are contradictory; no clear connection has been found between the level of autoantibodies to oxidized LDL and atherosclerosis. At the same time, there are facts indicating that the target of an autoimmune reaction may not be oxidized, but native LDL (nLDL). In particular, this is evidenced by the fact that the level of autoantibodies against nLDL in atherosclerosis is higher than in healthy people. Recent research findings indicate that autoimmune T cells recognizing apoprotein B100 epitopes of native LDL promote the development of atherosclerosis, whereas inhibition of the T cell response against native LDL suppresses the development of atherosclerosis. Therefore, it can be assumed that the cause of dyslipoproteinemia and atherogenesis is the development of an autoimmune reaction to native LDL. In accordance with this hypothesis, the development of an autoimmune reaction against nLDL in experimental animals should be accompanied by the appearance of dyslipoproteinemia and atherosclerotic changes in the vessel wall, similar to those observed in human atherosclerosis.
One way to induce autoimmune diseases in animals is to immunize them with a heterologous antigen, similar to the autoantigen. In this study, we attempted to induce an autoimmune reaction to nLDL in rats by immunizing them with native human low-density lipoproteins.
Purpose of the work: to test the hypothesis that an experimentally induced autoimmune reaction against native low-density lipoproteins in rats will be accompanied by metabolic and pathophysiological changes similar to changes in atherosclerosis in humans.
1. Develop a scheme for immunization of rats with native human low-density lipoproteins, causing a hyperimmune response against them.
2. To study the kinetics of antibodies to native human low-density lipoproteins, autoantibodies to native low-density lipoproteins, the level of low- and high-density lipoprotein cholesterol, total cholesterol in the serum of rats immunized with native human low-density lipoproteins.
3. Conduct a morphological and histological analysis of the heart and aortic arch in rats immunized with native human low-density lipoproteins.
Provisions for defense:
1. Immunization of rats with native human low-density lipoproteins causes an autoimmune reaction against native low-density lipoproteins, which is accompanied by the development of dyslipoproteinemia, an increase in the volume of perivascular, epicardial fat and atherosclerotic changes in the wall of the aortic arch.
2. Atherosclerosis in rats induced by immunization with native human low-density lipoproteins may be an adequate experimental model of human atherosclerosis.
Scientific novelty of the research
A new experimental model of rat atherosclerosis caused by immunization with native heterologous low-density lipoproteins has been developed. The experimental rat model of atherosclerosis reproduces the metabolic and pathophysiological changes characteristic of human atherosclerosis, such as dyslipidemia, increased volume of perivascular and epicardial fat, accumulation of leukocytes and lipid deposition in the vessel wall, media disorganization and intimal destruction, and therefore can be considered as an adequate model of human atherosclerosis. The results of the study provide new knowledge about the mechanisms of development
atherosclerosis, convincing facts were obtained in favor of the hypothesis about the leading role of the autoimmune reaction against nLDL in the development of dyslipoproteinemia and atherosclerosis. The experimental model has heuristic potential and opens up prospects for studying the cause-and-effect relationships between the processes involved in the pathogenesis of atherosclerosis; mechanisms of disruption of natural tolerance to nLDL, leading to atherosclerosis.
Practical significance of the study
The experimental model of atherosclerosis opens up the prospect of identifying early diagnostic markers of atherosclerosis, developing new diagnostic tools, therapy and assessing their effectiveness. The advantage of the rat model of atherosclerosis is reproducibility, cost-effectiveness, and ease of implementation. The experimental model of atherosclerosis can be used both in scientific research and in the educational process. The results of the study were introduced into the educational process in the special courses “Experimental Immunology”, “Clinical Immunology” of the master’s program “Immunobiotechnology” at the Faculty of Medical Biotechnology of the Federal State Budgetary Educational Institution of Higher Professional Education “Udmurt State University”.
Approbation of research results
The main provisions of the dissertation were reported and discussed at the VIII, X conferences of immunologists of the Urals “Current problems of fundamental and clinical immunology and allergology”, (Syktyvkar, 2010, Tyumen, 2012); XI International Correspondence Scientific and Practical Conference “Innovations in Science” (Novosibirsk, 2012); II All-Russian Scientific Conference of Young Scientists “Problems of Biomedical Science of the Third Millennium”, (St. Petersburg, 2012). 6 works have been published on the topic of the dissertation, including 4 articles in leading Russian peer-reviewed scientific journals included in the List of publications recommended by the Higher Attestation Commission of the Ministry of Education and Science of Russia.
Structure of the dissertation work.
The work is presented on 93 pages and consists of an introduction, a literature review, a description of materials and research methods, the results of one’s own research, their discussion, conclusions, and an appendix. The list of references includes 153 sources, including 13 domestic and 140 foreign. The work is illustrated with 22 drawings and 3 tables.
Similar dissertations in the specialty “Clinical immunology, allergology”, 03/14/09 code VAK
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The influence of environmental environmental factors on the prevalence of hypercholesterolemia and atherogenic dislipoproteinemia 2006, Candidate of Biological Sciences Sharapova, Natalia Vasilievna
Spectrum of mutational damage to the low-density lipoprotein receptor gene in the population of patients with familial hypercholesterolemia in St. Petersburg 1999, Candidate of Biological Sciences Shakir Hamid
On the possibility of using immunomodulators to correct alcohol motivation 2005, Candidate of Biological Sciences Kushnir, Ekaterina Aleksandrovna
Comparative assessment of the effectiveness of antiatherosclerotic effects of drugs of natural origin 1998, Candidate of Biological Sciences Khristich, Marina Nikolaevna
Conclusion of the dissertation on the topic “Clinical immunology, allergology”, Fomina, Ksenia Vladimirovna
1. A single immunization of Vistar rats with native human low-density lipoproteins at a dose of 200 μg in Freund's incomplete adjuvant induces in rats the production of autoantibodies against native rat low-density lipoproteins.
2. An autoimmune reaction against native low-density lipoproteins in rats is accompanied by the development of dyslipoproteinemia, the degree of dyslipoproteinemia depends on the level of production of autoantibodies against native low-density lipoproteins.
3. Dyslipoproteinemia in rats caused by immunization with native human low-density lipoproteins is accompanied by a decrease in the level of cholesteryl esters in the adrenal tissues, an increase in the volume of perivascular and epicardial white adipose tissue, the accumulation of leukocytes and lipid deposition in the wall of the aortic arch, destruction of the intima, thickening and exposure of the media.
4. Metabolic and pathophysiological changes induced in rats by immunization with native low-density lipoproteins are similar to early signs of the development of atherosclerosis in humans.
List of references for dissertation research Candidate of Biological Sciences Fomina, Ksenia Vladimirovna, 2013
Literature
1. Bobryshev Yu.V. Cellular mechanisms of atherosclerosis: innate immunity and inflammation / Yu.V. Bobryshev, V.P. Karagodin, Zh.I. Kovalevskaya, [etc.] // Fundamental sciences and practice. - 2010. - T. 1, No. 4. - pp. 140-148.
2. Vatutin N.T. Infection as a factor in the development of atherosclerosis and its complications / N.T. Vatutin, V.A. Chupina // Cardiology. - 2000. - No. 2. - P. 13-22.
3. Glanz S. Medical and biological statistics / S. Glanz. - M., 1999. - 459 p.
4. Gribanov G.A. Lipid analysis methods. Laboratory workshop for students of the Faculty of Chemistry and Biology / A.G. Gribanov; Kalinin State University. - Kalinin, 1980. - 51 p.
5. Klimov A.N. Autoimmune theory of the pathogenesis of atherosclerosis and new ways of its treatment / A.N. Klimov // Bulletin of the Russian Academy of Medical Sciences. -2003. -No. 12. -P.29-34.
6. Klimov A.N. Metabolism of lipids and lipoproteins and its disorders // A.N. Klimov, N.G. Nikulcheva. - St. Petersburg: Peter Kom, 1999. - 512 p.
7. Korepanov A.S. Idiotypic mechanisms regulating the development of an autoimmune reaction in an experimental model of autoimmune hemolytic anemia in mice / A.S. Korepanov, L.V. Beduleva, I.V. Menshikov, A.B. Knyazev // Bulletin of the Udmurt University. - 2012. -Episode 6. Biology. Geosciences. - No. 2. - P. 62-67.
8. Menshikov I.V. Autoimmune reactions in the pathogenesis of atherosclerosis / M.I. Makarova, N.I. Bulatova, L.V. Beduleva, N.H. Abisheva, M.G. Pozdeeva, H.A. Sidneva, A.A. Sannikova, E.V. Obukhova // Immunology. - 2010. - No. 5. -
9. Khlustov V.N. Autoimmune mechanisms in the pathogenesis of atherosclerosis // Advances in modern natural science. - 2007. - No. 12. - P. 66.
10. Khlustov V.N. Quantitative determination of autoantibodies to low-density lipoproteins / V. N. Khlustov // Clinical laboratory diagnostics. 1999. - No. 4. - pp. 17-20.
11. Khlustov V.N. Method for quantitative determination of autoantibodies to low-density lipoproteins in blood serum / V.N. Khlustov // Patent for invention. - No. 2137134. - 1999.
12. Chelnokova N.O. Clinical and morphological basis for modeling hemodynamics in the system of coronary arteries, taking into account their interaction with the myocardium: (review) / N.O. Chelnokova, A.A Golyadkina, O.A. Shchuchkina // Saratov Medical Scientific Journal. - 2011. - T.7, No. 4. - pp. 762-768.
13. Yarilin A.A. Fundamentals of immunology / A.A. Yarilin. - M.: Medicine, 1999 - 607 p.
14. Afek A. Immunization of low-density lipoprotein receptor deficient (LDL-RD) mice with heat shock protein 65 (HSP-65) promotes early atherosclerosis / A. Afek, J. George, B. Gilburd, L. Rauova, I Goldberg, J. Kopolovic, D. Harats, Shoenfeld Y. //J Autoimmun. - 2000. - 14. - P. 115-121.
15. Akishita M. Low testosterone level as a predictor of cardiovascular events in Japanese men with coronary risk factors / M. Akishita, M. Hashimoto, Y. Ohike, S. Ogawa, K. Iijima, M. Eto, Y. Ouchi / / Atherosclerosis. - 2010. - Vol. 210. -
16. Alagona P. Jr. Beyond LDL cholesterol: the role of elevated triglycerides and low HDL cholesterol in residual CVD risk remaining after statin therapy / P. Alagona Jr. // Am J Manag Care. - 2009. - Vol. 15. - P.65-73.
17. Alviar C.L. Infectious atherosclerosis: is the hypothesis still alive? A clinically based approach to the dilemma / C.L. Alviar, J. G. Echeverri, N.I. Jaramillo, C.J. Figueroa, J.P. Cordova, A. Korniyenko, J. Suh, A. Paniz-Mondolfi // Med Hypotheses. - 2011,- Vol. 76.-P. 517-521.
18. Animal Models for Autoimmune and Inflammatory Disease / Current Protocols in Immunology. - 1996. - by John Wiley & Sons, Inc.
19. Ayada K. Chronic infections and atherosclerosis / K. Ayada, K. Yokota, K. Kobayashi, Y. Shoenfeld, E. Matsuura, K. Oguma // Ann N Y Acad Sci. - 2007. -Vol. 1108. - P. 594-602.
20. Bachar G.N. Epicardial adipose tissue as a predictor of coronary artery disease in asymptomatic subjects / G.N. Bachar, D. Dicker, R. Kornowski, E. Atar // Am J Cardiol. - 2012. - Vol. 110. - P. 534-538.
21. Barter P. HDL-C: role as a risk modifier/ P. Barter //Atheroscler Suppl. - 2011. -Vol. 12.-P. 267-270.
22. Beduleva L. Role of idiotype-anti-idiotype interactions in the induction of collagen-induced arthritis in rats / L. Beduleva, I. Menshikov // Immunobiology. -2010.-Vol.215. - P. 963-970.
23. Blessing E. Chlamydia pneumoniae induces inflammatory changes in the heart and aorta of normocholesterolemic C57BL/6J mice / E. Blessing, T.M. Lin, L.A. Campbell, M.E. Rosenfeld, D. Lloyd, C. Kuo // Infect Immun. - 2000. - Vol. 68.-P. 4765^768.
24. Blouin K. Androgen metabolism in adipose tissue: recent advances / K. Blouin, A. Veilleux, V. Luu-The, A. Tchernof // My Cell Endocrinol. - 2009. - Vol. 301. -P. 97-103.
25. Borkowski A.J. Equilibration of plasma and adrenal cholesterol in man / A.J. Borkowski, S. Levin, C. Delcroix, J. Klastersky // J Appl Physiol. - 1970. - Vol. 28.-P. 42^9.
26. Boullier A. Detection of autoantibodies against oxidized low-density lipoproteins and of IgG-bound low density lipoproteins in patients with coronary artery disease / A. Boullier, M. Hamon, E. Walters-Laporte, F. Martin-Nizart, R Mackerel, J.C. Fruchart, M. Bertrand, P. Duriez // Clin Chim Acta. - 1995. - Vol. 238. - P. 1-10.
27. Buckley C.D. Why do leucocytes accumulate within chronically inflamed joints / C.D. Buckly // Rheumatology. - 2003. - Vol.42. - P. 1433-1444.
28. Che J. Serum autoantibodies against human oxidized low-density lipoproteins are inversely associated with the severity of coronary stenotic lesions calculated by Gensini score / J. Che, G. Li, W. Wang, Q. Li, H. Liu, K. Chen, T. Liu // Cardiol J. - 2011. -Vol. 18. - P. 364-370.
29. Chen X.H. Helicobacter pylori infection enhances atherosclerosis in high-cholesterol diet fed C57BL/6 mice / X.H. Chen, J.B. Wang, Y.S. Wang, Z.M Liu, Y. Li // Zhonghua Xin Xue Guan Bing Za Zhi. - 2010. - Vol. 38. - P. 259-263.
30. Chisolm G.M. The oxidative modification hypothesis of atherogenesis: an overview / G.M. Chisolm, D. Steinberg // Free Radic Biol Med. - 2000. - Vol. 28. -P. 1815-1826.
31. Corona G. Testosterone, cardiovascular disease and the metabolic syndrome / G. Corona, G. Rastrelli, L. Vignozzi, E. Mannucci, M. Maggi // Best Pract Res Clin Endocrinol Metab. - 2011. - Vol. 25. - P. 337-353.
32. Cziraky M.J. Targeting low HDL-cholesterol to decrease residual cardiovascular risk in the managed care setting / M.J. Cziraky, K.E. Watson, R.L. Talbert // J Manag Care Pharm. - 2008. - Vol. 14. - P. 3-28.
33. Daugherty A. Mouse models of atherosclerosis / A. Daugherty // Am J Med Sci. -2002.-Vol. 323.-P. 3-10.
34. De Pergola G. The adipose tissue metabolism: role of testosterone and dehydroepiandrosterone / G. De Pergola // Int J Obes Relat Metab Disord. - 2000. -Vol.24. - P. 59-63.
35. Dexter R.N. Stimulation of adrenal cholesterol uptake from plasma by adrenocorticotrophin / R.N. Dexter, L.M. Fishman, R.L. Ney // Endocrinology. -1970.- Vol.87. - P.836-846.
36. Djaberi R. Relation of epicardial adipose tissue to coronary atherosclerosis / R. Djaberi, J.D. Schuijf, J.M. van Werkhoven, et al. // Am J Cardiol. - 2008. - Vol. 102.-P. 1602-1607.
37. Drew A. Atherosclerosis. Experimental methods and protocols / A. Drew. - 243 c.
38. Engelmann M.G. Chronic perivascular inoculation with Chlamydophila pneumoniae results in plaque formation in vivo / M.G. Engelmann, C.V. Redl, J. Pelisek, C. Barz, J. Heesemann, S. Nikol // Lab Invest. - 2006. - Vol. 86. - P. 467-476.
39. Fabricant C.G. Virus-induced atherosclerosis/ C.G. Fabricant, J. Fabricant, M.M. Litrenta, C.R. Minick // J Exp Med. - 1978. - Vol. 148. - P. 335-340.
40. Fan J. Cholesterol-fed and transgenic rabbit models for the study of atherosclerosis / J. Fan, T. Watanabe // J Atheroscler Thromb. - 2000. - Vol. 7-P. 26-32.
41. Fazio S. Mouse models of hyperlipidemia and atherosclerosis / S. Fazio, M.F. Linton // Front Biosci. - 2001. - Vol. 6. - P. 515-525.
42. Franch A. Time course of antibodies against IgG and type II collagen in adjuvant arthritis. Role of mycobacteria administration in antibody production / A. Franch, S. Cassany, C. Castellote, M. Castell // Immunobiology. - 1994. - Vol. 190. - P. 93104.
43. Fukui M. Role of endogenous androgen against insulin resistance and atherosclerosis in men with type 2 diabetes / M. Fukui, Y. Kitagawa, H. Ose, G. Hasegawa, T. Yoshikawa, N. Nakamura // Curr Diabetes Rev. - 2007. - Vol. 3. - P. 25-31.
44. Fuster J.J. Animal models of atherosclerosis / J. J. Fuster, A.I. Castillo, C. Zaragoza, B. Ibanez, V. Andres // Prog Mol Biol Transi Sci. - 2012. - Vol. 105. -P. 1-23.
45. Galkina E. Immune and Inflammatory Mechanisms of Atherosclerosis / E. Galkina, K. Ley // Annu. Rev. Immunol. - 2009. - Vol. 27. - P. 165-197.
46. Galkina E. Lymphocyte recruitment into the aortic wall before and during development of atherosclerosis is partially L-selectin dependent / E. Galkina, A. Kadi, J. Sanders, D. Varughese, I. J. Sarembock, K. Ley // The Journal of Experimental Medicine. - 2006. - Vol. 203. - No. 5. - P. 1273-1282.
47. Gebbers J.O. Atherosclerosis, cholesterol, nutrition, and statins-a critical review / J.O. Gebbers // German Medical Science. - 2007. - Vol. 5. - Doc 04.
48. George J. Autoimmunity in atherosclerosis: lessons from experimental models / J. George, A. Afek, B. Gilburd, D. Harats, Y. Shoenfeld // Lupus. - 2000. - Vol. 9. -P. 223-227.
49. George J. Induction of early atherosclerosis in LDL-receptor-deficient mice immunized with beta2-glycoprotein I / J. George, A. Afek, B. Gilburd, M. Blank, Y. Levy, A. Aron-Maor, et al. // Circulation. - 1998. - Vol. 98. - P. 1108-1115.
50. Godfried S. Potentiation of atherosclerotic lesions in rabbits by a high dietary level of vitamin E / S. Godfried, G.F. Combs, J. Saroca, L.A. Dillingam // British Journal of Nutrition. - 1989. - Vol. 61. - P. 607-617.
51. Gounopoulos P. Antibodies to oxidized low density lipoprotein: epidemiological studies and potential clinical applications in cardiovascular disease / P. Gounopoulos, E. Merki, L.F. Hansen, S.H. Choi, S. Tsimikas // Minerva Cardioangiol. - 2007. -Vol. 55.-P. 821-837.
52. Grummer R.R. A review of lipoprotein cholesterol metabolism: importance to ovarian function / R.R. Grummer, D.J. Carroll // J.Anim.Sci. - 1988. - Vol. 66. -P.3160-3176.
53. Gwynne J. T. Adrenal cholesterol uptake from plasma lipoproteins: Regulation by Corticotropin / J. T. Gwynne, D. Mahaffee, H. B. Brewer, J. R., R. L. Ney // Proc. Natl. Acad. Sci. - 1976. - Vol. 73, no. 12. - P. 4329-4333.
54. Hadjiisky P. Experimental models of atherosclerosis. Contribution, limits and trends / P. Hadjiisky, M.C. Bourdillon, Y. Grosgogeat // Arch Mai Coeur Vaiss. -1991.-Vol. 84.-P. 1593-1603.
55. Hansson G.K. Atherosclerosis and the immune system / G. K. Hansson, G.P. Berne // Acta Paediatr Suppl. - 2004. - Vol. 93. - P. 63-69.
56. Hansson G.K. Atherosclerosis-an immune disease: The Anitschkov Lecture 2007 /G.K. Hansson // Atherosclerosis. - 2009. - Vol. 202. - P. 2-10.
57. Hansson G.K. Inflammation and immune response in atherosclerosis / G.K. Hansson//Curr Atheroscler Rep. - 1999.-Vol. 1. - P. 150-155.
58. Henrichot E. Production of chemokines by perivascular adipose tissue: a role in the pathogenesis of atherosclerosis? / E. Henrichot, C.E. Juge-Aubry, A. Pernin, J.C. Pache, V. Velebit, J.M. Dayer, P. Meda, C. Chizzolini, C.A. Meier // Arterioscler Thromb Vase Biol. - 2005. - Vol. 25. - P. 2594-2599.
59. Hermansson A. Inhibition of T cell response to native low density lipoprotein reduces atherosclerosis / A. Hermansson, D. Ketelhuth, D. Strodthoff, et al. // J Exp Med. - 2010. - Vol. 207. - P. 1081-1093.
60. Holoshitz J. Arthritis induced in rats by cloned T lymphocytes responsive to
mycobacteria but not to collagen type II / J. Holoshitz, A. Matitiau, I. R. Cohen // J Clin Invest. - 1984. - Vol. 73. - P. 211-215.
61. Hulthe J. Antibody titers against oxidized LDL are not elevated in patients with familial hypercholesterolemia / J. Hulthe, J. Wikstrand, A. Lidell, I. Wendelhag, G.K. Hansson, O. Wiklund // Arterioscler Thromb Vase Biol. - 1998. - Vol. 18. -P. 1203-1211.
62. Iacobellis G. Epicardial adipose tissue: anatomic, biomolecular and clinical relationships with the heart/ G. Iacobellis, D. Corradi, A.M. Sharma // Nat Clin Pract Cardiovasc Med. - 2005. - Vol. 2. - P.536-543.
63. Iacobellis G. Epicardial adipose tissue: physiological emerging, pathophysiological and clinical features / G. Iacobellis, A.C. Bianco // Trends Endocrinol Metab. - 2011. - Vol. 22. - P.450-457.
64. Imaizumi K. Diet and atherosclerosis in apolipoprotein E-deficient mice / K. Imaizumi // Biosci Biotechnol Biochem. - 2011. - Vol. 75. - P. 1023-1035.
65. Jawien J. Mouse models of experimental atherosclerosis / J. Jawien, P. Nastalek, R. Korbut // J Physiol Pharmacol. - 2004. - Vol. 55. - P. 503-517.
66. Jiang X. Oxidized low density lipoproteins~do we know enough about them? / X. Jiang, Z. Yang, A.N. Chandrakala, D. Pressley, S. Parthasarathy // Cardiovasc Drugs Ther.-2011,- Vol. 25. - P. 367-377.
67. Karabinos I. Increased serum titers of autoantibodies against oxidized LDL cholesterol in young healthy adults /1. Karabinos, S. Koulouris // Atherosclerosis. -2007. - Vol. 192. - P. 448-450.
68. Kern J.M. Chlamydia pneumoniae-induced pathological signaling in the vasculature / J.M. Kern, V. Maass, M. Maass // FEMS Immunol Med Microbiol. -2009.-Vol. 55. - P.131-139.
69. Kojic Z.Z. Animal models in the study of atherosclerosis / Z.Z. Kojic // Srp Arh Celok Lek. -2003. - Vol. 131. - P. 266-270.
70. Kruif M.D. Chlamydia pneumoniae infections in mouse models: relevance for atherosclerosis research / M.D. de Kruif, E.C. van Gorp, T.T. Keller, J.M. Ossewaarde, H. ten Cate // Cardiovasc Res. - 2005. - Vol. 65. - P. 317-327.
71. Kruth H.S. Macropinocytosis is the endocytic pathway that mediates macrophage foam cell formation with native low density lipoprotein / H.S. Kruth, N.L. Jones, W. Huang, B. Zhao, I. Ishii, J. Chang, C.A. Combs, D. Malide, W.Y. Zhang // J Biol Chem. - 2005. - Vol. 280. - P. 2352-2360.
72. Kruth H.S. Receptor-independent fluid-phase pinocytosis mechanisms for induction of foam cell formation with native low-density lipoprotein particles / H.S. Kruth // Curr Opin Lipidol. - 2011. - Vol. 22. - P. 386-393.
73. Krysiak R. Current views on the role of dehydroepiandrosterone in physiology, pathology and therapy / R. Krysiak, D. Frysz-Naglak, B. Okopien // Pol Merkur Lekarski. - 2008. - Vol. 24. - P. 66-71.
74. Kurano M. Etiology of atherosclerosis-special reference to bacterial infection and viral infection / M. Kurano, K. Tsukamoto // Nihon Rinsho. - 2011. - Vol. 69. -P. 25-29.
75. Leinonen J.S. The level of autoantibodies against oxidized LDL is not associated with the presence of coronary heart disease or diabetic kidney disease in patients with non-insulin-dependent diabetes mellitus / J.S. Leinonen, V. Rantalaiho, P. Laippala, O. Wirta, A. Pasternack, H. Alho, O. Jaakkola, S. Yla-Herttuala, T. Koivula, T. Lehtimaki // Free Radic Res. - 1998. - Vol. 29. - P. 137-141.
76. Li J.Z. A long-term follow-up study of serum lipid levels and coronary heart disease in the elderly / J.Z. Li, M. L. Chen, S. Wang, J. Dong, P. Zeng, L.W. Hou // Chin Med J. - 2004. - Vol. 117. P. 163-167.
77. Libby P. Inflammation in Atherosclerosis: Transition From Theory to Practice / P. Libby, Y. Okamoto, V.Z. Rocha, et al. // Circ J. 2010. - Vol. 74. - P. 213-220.
78. Liuba P. Acute Chlamydia pneumoniae infection causes coronary endothelial dysfunction in pigs / P. Liuba, E. Pesonen, I. Paakkari, S. Batra, A. Forslid, P. Kovanen et al. // Atherosclerosis. - 2003. - Vol. 167. - P. 215-222.
79. Lopes-Virella M.F. Atherosclerosis and autoimmunity / M.F. Lopes-Virella, G. Virella // Clin Immunol Immunopathol. - 1994. - Vol. 73. - P. 155-167.
80. Maggio M. Welcoming low testosterone as a cardiovascular risk factor / M. Maggio, S. Basaria // Int J Impot Res. - 2009. - Vol. 21. - P. 261-264.
81. Mahabadi A.A. Association of pericoronary fat volume with atherosclerotic plaque burden in the underlying coronary artery: a segment analysis / A.A Mahabadi, N. Reinsch, N. Lehmann, J. Altenbernd, H. Kalsch, R.M. Seibel, R. Erbel, S. Mohlenkamp // Atherosclerosis. - 2010. - Vol. 211. - P. 195-199.
82. Mammi C. Androgens and Adipose Tissue in Males: A Complex and Reciprocal Interplay / C. Mammi, M. Calanchini, A. Antelmi, F. Cinti, G. Rosano, A. Lenzi, M. Caprio, A. Fabbri / / International Journal of Endocrinology. - 2012. -doi:10.1155/2012/789653
83. Mandal K. Autoimmune mechanisms of atherosclerosis / K. Mandal, M. Jahangiri, Q. Xu // Handb Exp Pharmacol. - 2005. - Vol. 170. - P. 723-743.
84. McNamara D. J. Dietary cholesterol and atherosclerosis / D. J. McNamara // Biochim Biophys Acta. - 2000. - Vol. 1529. - P. 310-320.
85. Medras M. Testosterone and dehydroepiandrosterone deficiency, general adiposity and visceral obesity during normal male aging / M. Medras, E.A. Jankowska // Pol Merkur Lekarski. - 2001. - Vol. 11. - P. 187-190.
86. Meier C.A. White adipose tissue, inflammation and atherosclerosis / C.A. Meier, S. Thalmann // Bull Acad Natl Med. - 2007. -Vol. 191. - P. 897-908.
87. Menshikov I. Evidence in favor of a role of idiotypic network in autoimmune hemolytic anemia induction: theoretical and experimental studies / I. Menshikov, L. Beduleva // Int Immunol. - 2008. - Vol. 20. - P. 193-198.
88. Mironova M. Isolation and characterization of human antioxidized LDL autoantibodies./ M. Mironova, G. Virella, M.F. Lopes-Virella // Arterioscler Thromb Vase Biol. - 1996. - Vol. 16. - P. 222-229.
89. Moghadasian M.H. Experimental atherosclerosis: a historical overview / M.H. Moghadasian // Life Sci. - 2002. - Vol.70. - P. 855-865.
90. Mussa F.F. Chlamydia pneumonia and vascular disease: an update / F.F. Mussa, H. Chai, X. Wang, Q. Yao, A.B. Lumsden, C. Chen // J Vase Surg. - 2006. - Vol. 43. -P. 1301-1307.
91. Nandakumar K.S. Collagen type II (Cll)-specific antibodies induce arthritis in the absence of T or B cells but the arthritis progression is enhanced by Cll-reactive
T cells/K.S. Nandakumar, J. Backlund, M. Vestberg // Arthritis Res Ther. - 2004. -Vol. 6. - P. 544-550.
92. Nilsson J. The B cell in atherosclerosis: teaming up with the bad guys? / J. Nilsson, G.N. Fredrikson // Clin Chem. - 2010. - Vol. 56. - P. 1789-1791.
93. Ohman M.K. Perivascular visceral adipose tissue induces atherosclerosis in apolipoprotein E deficient mice / M.K. Ohman, W. Luo, H. Wang, C. Guo, W. Abdallah, H. M. Russo, D. T. Eitzman // Atherosclerosis. - 2011. - Vol. 219. -P. 33-39.
94. Ouwens D.M. The role of epicardial and perivascular adipose tissue in the pathophysiology of cardiovascular disease / D.M. Ouwens, H. Sell, S. Greulich, J. Eckel // J Cell Mol Med. - 2010. - Vol. 14. - P. 2223-2234.
95. Palinski W. Antisera and monoclonal antibodies specific for epitopes generated during the oxidative modification of low density lipoprotein // W. Palinski, S. Yla-Herttuala, M.E. Rosenfeld, S. Butler, S.A. Socher, S. Parthasarathy, L. K. Curtiss, J. L. Witztum // Arteriosclerosis. - 1990. - Vol. 10. - P. 325-335.
96. Parthasarathy S. Atherogenesis / S. Parthasarathy. - C.507
97. Parthasarathy S. Oxidized low-density lipoprotein, a two-faced Janus in coronary artery disease? / S. Parthasarathy, N. Santanam, N. Auge // Biochem Pharmacol. -1998.-Vol. 56.-P. 279-284.
98. Pasqui A.L. Immune factors in atherosclerosis / A.L. Pasqui, G. Bova, S. Maffei, A. Auteri//Ann Ital Med Int. -2005.-Vol. 20.-P.81-89.
99. Payne G.A. Epicardial perivascular adipose tissue as a therapeutic target in obesity-related coronary artery disease / G.A. Payne, M.C. Kohr, J.D. Tune // Br J Pharmacol. - 2012. - Vol. 165. - P. 659-669.
100. Rabkin S.W. Epicardial fat: properties, function and relationship to obesity / S.W. Rabkin // Obes Rev. - 2007. - Vol. 8. - P. 253-261.
101. Ravnskov U. A hypothesis out-of-date: The diet-heart idea / U. Ravnskov // Journal of Clinical Epidemiology. - 2002. - 55. - P. 1057-1063.
102. Ravnskov U. The fallacies of the lipid hypothesis / U. Ravnskov // Scand Cardiovasc J. - 2008. - Vol. 42. - P. 236-239.
103. Ritskes-Hoitinga J. Atherosclerosis in the rat / J. Ritskes-Hoitinga, A.C. Beynen //Artery. - 1988.-Vol. 16.-P. 25-50.
104. Rose N.R Infection, mimics, and autoimmune disease / N.R. Rose // J Clin Invest. - 2001. - Vol. 107. - P. 943-944.
105. Rossi G.P. Antibodies to oxidized low-density lipoproteins and angiographically assessed coronary artery disease in white patients / G.P. Rossi, M. Cesari, R. De Toni, M. Zanchetta, G. Maiolino, L. Pedon, C. Ganzaroli, P. Maiolino, A.C. Pessina // Circulation. - 2003. - Vol. 108. - P. 2467-2472.
106. Sacks H.S. Human epicardial adipose tissue: a review / H.S. Sacks, J.N. Fain // Am Heart J. - 2007. - Vol. 153. - P. 907-917.
107. Saikku P. Serological evidence of an association of a novel Chlamydia, TWAR, with coronary heart disease and acute myocardial infarction / P. Saikku, K. Mattila, M.S. Nieminen et al. // Lancet. - 1988. - Vol.2. - P. 983-986.
108. Sarin S. Clinical significance of epicardial fat measured using cardiac multislice computed tomography / S. Sarin, C. Wenger, A. Marwaha, A. Qureshi, B.D. Go, C.A. Woomert, K. Clark, L.A. Nassef, J. Shirani // Am J Cardiol. - 2008. - Vol. 102. -P. 767-771.
109. Shah P.K. Residual risk and high-density lipoprotein cholesterol levels: is there a relationship? /P.K. Shah // Rev Cardiovasc Med. - 2011. - Vol. 12. - P. 55-59.
110. Shi G. P. Immunomodulation of vascular diseases: atherosclerosis and autoimmunity/ G.P. Shi // Eur J Vase Endovasc Surg. - 2010. - Vol. 39. - P. 485-494.
111. Singh V. Models to Study Atherosclerosis: A Mechanistic Insight / V. Singh, R.L. Tiwari, M. Dikshit, M.K. Barthwal // Current Vascular Pharmacology. - 2009. -Vol. 7.-P. 75-109.
112. Spagnoli L.G. Role of Inflammation in Atherosclerosis / L.G. Spagnoli, E. Bonanno // The Journal of Nuclear Medicine. - Vol. 48, No. 11. - P. 1800-1815.
113. Spence J.D. Infection, Inflammation, and Atherosclerosis / J. D. Spence, J. Norris // Stroke. - 2003. - Vol. 34. - P.333-334.
114. Spiroglou S.G. Adipokines in periaortic and epicardial adipose tissue: differential expression and relation to atherosclerosis / S.G. Spiroglou,
C. G. Kostopoulos, J. N. Varakis, H.H. Papadaki // J Atheroscler Thromb. - 2010. -Vol. 17.-P. 115-130.
115. Stassen F.R. Infection and atherosclerosis. An alternative view on an outdated hypothesis / F.R. Stassen, T. Vainas, C.A. Bruggeman // Pharmacol Rep. - 2008. -Vol. 60. - P. 85-92.
116. Steinberg D. The LDL modification hypothesis of atherogenesis: an update /
D. Steinberg // J. Lipid Res. - 2009. - Vol. 50. - P. 376-381.
117. Steinberg D. An interpretive history of the cholesterol controversy: part I / D. Steinberg // Journal of Lipid Research. - 2004. - Vol. 45. - P. 1583-1593.
118. Steinberg D. An interpretive history of the cholesterol controversy: part II: the early evidence linking hypercholesterolemia to coronary disease in humans / D. Steinberg // Journal of Lipid Research. - 2004. - Vol. 46. - P. 179-190.
119. Stocker R. Role of oxidative modifications in atherosclerosis / R. Stocker, J.F. Keaney Jr. // Physiol Rev. - 2004. - Vol. 84. - P. 1381-1478.
120. Streblow D.N. Do pathogens accelerate atherosclerosis? / D.N. Streblow, S. L. Orloff, J.A. Nelson // J Nutr. - 2001. - Vol. 131. - P. 2798-2804.
121. Sulzer B., Central immune system, the self and autoimmunity / B. Sulzer, J. Van Hemmen, U. Behn // Bull. Math. Biol. - 1994. - Vol. 56. - P. 1009-1040.
122. Swanborg, R.H. Animal models of human disease. Experimental autoimmune encephalomyelitis in rodents as a model for human demyelinating disease / R.H. Swanborg // Clin. Immunol. Immunopathol. - 1995. - Vol. 77. - P. 4-13.
123. Szasz T. Perivascular adipose tissue: more than just structural support / T. Szasz, R.C. Webb // Clin Sci (Lond). - 2012. - Vol. 122. - P. 1-12.
124. Takahashi M. Inflammatory cytokines in the pathogenesis of atherosclerosis / M. Takahashi / Nihon Rinsho. - 2011. - Vol. 69. - P. 30-33.
125. Thalmann S. Local adipose tissue depots as cardiovascular risk factors / S. Thalmann, C.A. Meier // Cardiovasc Res. - 2007. - Vol. 75. - P.690-701.
126. Thompson G.R. History of the cholesterol controversy in Britain / G.R. Thompson //QJM. - 2009. - Vol. 102. - P.81-86.
127. Traish A. M. Dehydroepiandrosterone (DHEA) - a precursor steroid or an active hormone in human physiology / A.M. Traish, H.P. Kang, F. Saad, A.T. Guay // J Sex Med. - 2011. - Vol. 8. - P. 2960-2982.
128. Traish A.M. Testosterone and cardiovascular disease: an old idea with modern clinical implications / A.M. Traish, K.E. Kypreos // Atherosclerosis. - 2011. -Vol. 214(2).-P. 244-248.
129. Trentham D.E. Humoral and Cellular Sensitivity to Collagen in Type II Collagen-Induced Arthritis in Rats / D.E. Trentham, A. Townes, H. Andrew, J. R. David // J Clin Invest. - 1978. - Vol. 61. - P. 89-96.
130. Tsai W.C. Relation between antibody against oxidized low-density lipoprotein and extent of coronary atherosclerosis / W.C. Tsai, Y.H. Li, T.H. Chao, J.H. Chen // J Formos Med Assoc. - 2002. - Vol. 101. - P. 681-684.
131. Turk J.R. Physical activity and atherosclerosis: which animal model? /J.R. Turk, M. H. Laughlin // Can J Appl Physiol. - 2004. - Vol. 29. - P. 657-683.
132. Tuttolomondo A. Atherosclerosis as an Inflammatory Disease / A. Tuttolomondo, D. Di Raimondo, R. Pecoraro, V. Arnao, A. Pinto, G. Licata // Curr Pharm Des. - 2012. - Vol. 18. - P. 4266-4288.
133. Uusitupa M.I. Autoantibodies against oxidized LDL do not predict atherosclerotic vascular disease in non-insulin-dependent diabetes mellitus / M.I. Uusitupa, L. Niskanen, J. Luoma, P. Vilja, M. Mercuri, R. Rauramaa, S. Ylä-Herttuala // Arterioscler Thromb Vase Biol. - 1996. - Vol. 16. - P. 1236-1242.
134. Vanderlaan P.A. Thematic review series: the immune system and atherogenesis. The unusual suspects:an overview of the minor leukocyte populations in atherosclerosis / P.A. Vanderlaan, C.A. Reardon // J Lipid Res. - 2005. - Vol. 46. -P. 829-838.
135. Veniant M.M. Lipoprotein size and atherosclerosis susceptibility in Apoe(-/-) and Ldlr(-/-) mice / M.M. Veniant, S. Withycombe, S.G. Young // Arterioscler Thromb Vase Biol. - 2001. - Vol. 21. - P. 1567-1570.
136. Verhagen S.N. Perivascular adipose tissue as a cause of atherosclerosis / S.N. Verhagen, F. L. Visseren // Atherosclerosis. - 2011. - Vol. 214. - P. 3-10.
137. Virella G. Atherogenesis and the humoral immune response to modified lipoproteins / G. Virella, M.F. Lopes-Virella // Atherosclerosis. - 2008. - Vol. 200. -P. 239-246.
138. Wang J.-L. Correlation of Inflammatory Cells in Adventitia and Formation and Extending of Atherosclerotic Lesions in Coronary Artery of Apolipoprotein E Gene Knockout Mice / J-L. Wang, S.-Q. Ma, L. Li, G-Q. Liu, Wei-C. Hu, R. Ma // Chinese Journal of Physiology. - 2012. - Vol. 56. - doi: 10.4077/CJP.2013.BAA080.
139. Weverling-Rijnsburger A.W. High-density vs low-density lipoprotein cholesterol as the risk factor for coronary artery disease and stroke in old age / A.W. Weverling-Rijnsburger, I.J. Jonkers, E. van Exel, J. Gussekloo, R.G. Westendorp // Arch Intern Med. - 2003. - Vol. 163. - P. 1549-1554.
140. Wick G. Role of heat shock protein 65/60 in the pathogenesis of atherosclerosis / G. Wick, R. Kleindienst, G. Schett, A. Amberger, Q. Xu // Int Arch Allergy Immunol. - 1995.-Vol. 107. - P. 130-131.
141. William R. Ware The mainstream hypothesis that LDL cholesterol drives atherosclerosis may have been falsified by non-invasive imaging of coronary artery plaque burden and progression / R. William // Med Hypotheses. - 2009. - Vol. 73. -P. 596-600.
142. Wozniak S.E. Adipose tissue: the new endocrine organ? A review article / S.E. Wozniak, L.L. Gee, M.S. Wachtel, E.E. Frezza // Dig Dis Sci. - 2009. -Vol. 54. - P.1847-1856.
143. Wucherpfennig K. W. Mechanisms for the induction of autoimmunity by infectious agents / K. W. Wucherpfennig // J Clin Invest. - 2001. - Vol. 108. -P. 1097-1104.
144. Xu F. Adventitial fibroblasts are activated in the early stages of atherosclerosis in the apolipoprotein E knockout mouse / F. Xu, J. Ji, L. Li, R. Chen, W.C. Hu // Biochem Biophys Res Commun. - 2007. - Vol. 352. - P. 681-688.
145. Xu Q. Mouse models of arteriosclerosis: from arterial injuries to vascular grafts / Q. Xu // Am J Pathol. - 2004. - Vol. 165 - P. 1-10.
146. Yanni A.E. The laboratory rabbit: an animal model of atherosclerosis research / A.E. Yanni // Lab Anim. - 2004. - Vol. 38. - P. 246-256.
147. Yerramasu A. Increased volume of epicardial fat is an independent risk factor for accelerated progression of sub-clinical coronary atherosclerosis / A. Yerramasu, D. Dey, S. Venuraju, D.V. Anand, S. Atwal, R. Corder, D.S. Berman, A. Lahiri // Atherosclerosis. - 2012. - Vol. 220. - P. 223-230.
148. Yorgun H. Epicardial adipose tissue thickness predicts descending thoracic aorta atherosclerosis shown by multidetector computed tomography / H. Yorgun, U. Canpolat, T. Hazirolan et al. // Int J Cardiovasc Imaging. - 2012. - Vol. 28. -P. 911-919.
149. Yoshida H. Front line of oxidized lipoproteins: role of oxidized lipoproteins in atherogenesis and cardiovascular disease risk/ H. Yoshida // Rinsho Byori. -2010. -Vol. 58. - P. 622-630.
150. Zaragoza C. Animal Models of Cardiovascular Diseases / C. Zaragoza, C. Gomez-Guerrero, J.L. Martin-Ventura et al. // Journal of Biomedicine and Biotechnology. -2011. -doi:10.1155/2011/497841.
151. Zhao D. Oxidized Low-Density Lipoprotein and Autoimmune Antibodies in Patients With Antiphospholipid Syndrome With a History of Thrombosis / D. Zhao, H. Ogawa, X. Wang, G. S. Cameron, D. E. Baty, J. S. Dlott, D. A. Triplett // Am J Clin Pathol. - 2001. - Vol. 116. - P. 760-767.
152. Zhao Q. Inflammation, autoimmunity, and atherosclerosis / Q. Zhao // Discov Med. - 2009. - Vol. 8. - P. 7-12.
153. URL: http://www.kalenbiomed.com/34product_oldl.html (accessed 10/01/12).
The study was supported by the Federal Target Program of the Ministry of Education and Science of the Russian Federation, agreement No. 14.B37.21.0211; AVTSP of the Ministry of Education and Science of the Russian Federation “RNPVSh (2009-2011)”, No. 2.1.1/2157; state order of the Ministry of Education and Science of the Russian Federation for research on the topic “Autoimmune mechanisms of atherosclerosis. New experimental model of atherosclerosis in rats” No. 4.5505.2011.
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The original meaning of the concept "atherosclerosis", proposed by Marchand in 1904, came down to only two types of changes: the accumulation of fatty substances in the form of mushy masses in the inner lining of the arteries (from the Greek athere - porridge) and sclerosis itself - a connective tissue thickening of the artery wall (from the Greek scleras - hard). The modern interpretation of atherosclerosis is much broader and includes ... “various combinations of changes in the intima of the arteries, manifested in the form of focal deposition of lipids, complex carbohydrate compounds, blood elements and products circulating in it, the formation of connective tissue and calcium deposition” (WHO definition).
Sclerotic vessels (the most common location is the aorta, arteries of the heart, brain, lower extremities) are characterized by increased density and fragility. Due to a decrease in elastic properties, they are not able to adequately change their lumen depending on the need of an organ or tissue for blood supply.
Initially, the functional inferiority of sclerotically altered vessels, and therefore organs and tissues, is detected only when increased demands are placed on them, i.e., when the load increases. Further progression of the atherosclerotic process can lead to decreased performance at rest.
A strong degree of atherosclerotic process is usually accompanied by narrowing and even complete closure of the lumen of the arteries. With the slow sclerosis of arteries in organs with impaired blood supply, atrophic changes occur with the gradual replacement of functionally active parenchyma by connective tissue.
Rapid narrowing or complete closure of the lumen of the artery (in the case of thrombosis, thromboembolism or hemorrhage into the plaque) leads to necrosis of the organ area with impaired blood circulation, i.e. to a heart attack. Myocardial infarction is the most common and most dangerous complication of atherosclerosis of the coronary arteries.
Experimental models. In 1912, N. N. Anichkov and S. S. Khalatov proposed a method for modeling atherosclerosis in rabbits by introducing cholesterol inside (through a tube or by mixing it with regular food). Pronounced atherosclerotic changes developed after several months with daily use of 0.5 - 0.1 g of cholesterol per 1 kg of body weight. As a rule, they were accompanied by an increase in the level of cholesterol in the blood serum (3-5 times compared to the initial level), which was the basis for the assumption of a leading pathogenetic role in the development of atherosclerosis hypercholesterolemia. This model is easily reproducible not only in rabbits, but also in chickens, pigeons, monkeys, and pigs.
In dogs and rats resistant to cholesterol, atherosclerosis is reproduced by the combined effect of cholesterol and methylthiouracil, which suppresses thyroid function. This combination of two factors (exogenous and endogenous) leads to prolonged and severe hypercholesterolemia (over 26 mmol/l - 100 mg%). Adding butter and bile salts to food also contributes to the development of atherosclerosis.
In chickens (roosters), experimental atherosclerosis of the aorta develops after long-term (4 - 5 months) exposure to diethylstilbestrol. In this case, atherosclerotic changes appear against the background of endogenous hypercholesterolemia, resulting from a violation of the hormonal regulation of metabolism.
Etiology. The given experimental examples, as well as observations of spontaneous human atherosclerosis and its epidemiology, indicate that this pathological process develops as a result of the combined action of a number of factors (environmental, genetic, nutritional). In each individual case, one of them comes to the fore. There are factors that cause atherosclerosis and factors that contribute to its development.
On rice. 19.12 a list of the main etiological factors (risk factors) of atherogenesis is given. Some of them (heredity, gender, age) are endogenous. They manifest their effect from the moment of birth (gender, heredity) or at a certain stage of postnatal ontogenesis (age). Other factors are exogenous. The human body encounters their effects at various age periods.
The role of hereditary factors The occurrence of atherosclerosis is confirmed by statistical data on the high incidence of coronary heart disease in individual families, as well as in identical twins. We are talking about hereditary forms of hyperlipoproteinemia, genetic abnormalities of cellular receptors for lipoproteins.
Floor. At the age of 40 - 80 years, men suffer from atherosclerosis and myocardial infarction of an atherosclerotic nature more often than women (on average 3 - 4 times). After 70 years, the incidence of atherosclerosis among men and women is approximately the same. This indicates that the incidence of atherosclerosis among women occurs at a later period. These differences are associated, on the one hand, with a lower initial level of cholesterol and its content mainly in the fraction of non-atherogenic a-lipoproteins in the blood serum of women, and on the other, with the anti-sclerotic effect of female sex hormones. A decrease in the function of the gonads due to age or for any other reason (removal of the ovaries, their irradiation) causes an increase in serum cholesterol levels and a sharp progression of atherosclerosis.
It is assumed that the protective effect of estrogens is reduced not only to the regulation of cholesterol in the blood serum, but also other types of metabolism in the arterial wall, in particular oxidative. This anti-sclerotic effect of estrogens manifests itself mainly in relation to the coronary vessels.
Age. A sharp increase in the frequency and severity of atherosclerotic vascular lesions due to age, especially noticeable after 30 years (see. rice. 19.12), gave rise to some researchers the idea that atherosclerosis is a function of age and is an exclusively biological problem [Davydovsky I.V., 1966]. This explains the pessimistic attitude towards a practical solution to the problem in the future. Most researchers, however, are of the opinion that age-related and atherosclerotic changes in blood vessels are various forms of arteriosclerosis, especially in the later stages of their development, but age-related changes in blood vessels contribute to its development. The effect of age, which promotes atherosclerosis, manifests itself in the form of local structural, physicochemical and biochemical changes in the arterial wall and general metabolic disorders (hyperlipemia, hyperlipoproteinemia, hypercholesterolemia) and its regulation.
Excessive nutrition. Experimental studies by N. N. Anichkov and S. S. Khalatov suggested the importance of the etiological role in the occurrence of spontaneous atherosclerosis of excess nutrition, in particular, excess intake of dietary fats. The experience of countries with a high standard of living convincingly proves that the more energy needs are met through animal fats and cholesterol-containing foods, the higher the cholesterol level in the blood and the incidence of atherosclerosis. On the contrary, in countries where animal fats account for a small part of the energy value of the daily diet (about 10%), the incidence of atherosclerosis is low (Japan, China).
In accordance with the program developed in the USA, based on these facts, reducing fat intake from 40% of total calories to 30% by the year 2000 should reduce mortality from myocardial infarction by 20 - 25%.
Stress. The incidence of atherosclerosis is higher among people in “stressful professions,” i.e. professions that require prolonged and strong nervous tension (doctors, teachers, lecturers, administrative staff, pilots, etc.).
In general, the incidence of atherosclerosis is higher among the urban population compared to the rural population. This can be explained by the fact that in a big city a person is more often exposed to neurogenic stress influences. Experiments confirm the possible role of neuropsychic stress in the occurrence of atherosclerosis. The combination of a high-fat diet with nervous tension should be considered unfavorable.
Physical inactivity. A sedentary lifestyle and a sharp decrease in physical activity (hypodynamia), characteristic of humans in the second half of the 20th century, are another important factor in atherogenesis. This position is supported by the lower incidence of atherosclerosis among manual workers and the higher incidence among people engaged in mental work; faster normalization of cholesterol levels in the blood serum after its excess intake from the outside under the influence of physical activity.
The experiment revealed pronounced atherosclerotic changes in the arteries of rabbits after placing them in special cages, which significantly reduced their motor activity. A combination of a sedentary lifestyle and excess nutrition poses a particular atherogenic danger.
Intoxication. The influence of alcohol, nicotine, intoxication of bacterial origin and intoxication caused by various chemicals (fluorides, CO, H 2 S, lead, benzene, mercury compounds) are also factors contributing to the development of atherosclerosis. In most of the intoxications examined, not only general disorders of fat metabolism characteristic of atherosclerosis were noted, but also typical dystrophic and infiltrative-proliferative changes in the arterial wall.
Arterial hypertension Apparently, it does not have independent significance as a risk factor. This is evidenced by the experience of countries (Japan, China), whose population often suffers from hypertension and rarely from atherosclerosis. However, high blood pressure is becoming a contributing factor to the development of atherosclerosis.
factor in combination with others, especially if it exceeds 160/90 mm Hg. Art. Thus, with the same cholesterol level, the incidence of myocardial infarction with hypertension is five times higher than with normal blood pressure. In an experiment on rabbits whose food was supplemented with cholesterol, atherosclerotic changes develop faster and reach a greater extent against the background of hypertension.
Hormonal disorders, metabolic diseases. In some cases, atherosclerosis occurs against the background of previous hormonal disorders (diabetes mellitus, myxedema, decreased function of the gonads) or metabolic diseases (gout, obesity, xanthomatosis, hereditary forms of hyperlipoproteinemia and hypercholesterolemia). The etiological role of hormonal disorders in the development of atherosclerosis is also evidenced by the above experiments on the experimental reproduction of this pathology in animals by influencing the endocrine glands.
Pathogenesis. Existing theories of the pathogenesis of atherosclerosis can be reduced to two, fundamentally different in their answers to the question: what is primary and what is secondary in atherosclerosis, in other words, what is the cause and what is the consequence - lipoidosis of the inner lining of the arteries or degenerative-proliferative changes in the latter. This question was first raised by R. Virchow (1856). He was the first to answer it, pointing out that “under all conditions, the process probably begins with a certain loosening of the connective tissue basic substance, of which the inner layer of the arteries mostly consists.”
Since then, the idea of the German school of pathologists and its followers in other countries began, according to which, with atherosclerosis, dystrophic changes in the inner lining of the artery wall initially develop, and the deposition of lipids and calcium salts is a secondary phenomenon. The advantage of this concept is that it is able to explain the development of spontaneous and experimental atherosclerosis both in cases where there are pronounced disorders of cholesterol metabolism, and in their absence. The authors of this concept assign a primary role to the arterial wall, i.e., the substrate that is directly involved in the pathological process. “Atherosclerosis is not only and not so much a reflection of general metabolic changes (in the laboratory they can even be elusive), but rather a derivative of the own structural, physical and chemical transformations of the substrate of the arterial wall... The primary factor leading to atherosclerosis lies precisely in the arterial wall itself , in its structure and in its enzyme system" [Davydovsky I.V., 1966].
In contrast to these views, since the experiments of N.N. Anichkov and S.S. Khalatov, mainly thanks to the research of domestic and American authors, the concept of the role in the development of atherosclerosis of general metabolic disorders in the body, accompanied by hypercholesterolemia, hyper- and dyslipoproteinemia, has been successfully developed. From this point of view, atherosclerosis is a consequence of the primary diffuse infiltration of lipids, in particular cholesterol, into the unchanged inner lining of the arteries. Further changes in the vascular wall (the phenomena of mucoid edema, dystrophic changes in the fibrous structures and cellular elements of the subendothelial layer, productive changes) develop due to the presence of lipids in it, i.e. they are secondary.
Initially, the leading role in increasing the level of lipids, especially cholesterol, in the blood was attributed to the nutritional factor (excessive nutrition), which gave the name to the corresponding theory of the occurrence of atherosclerosis - nutritional. However, very soon it had to be supplemented, since it became obvious that not all cases of atherosclerosis can be put in a causal relationship with nutritional hypercholesterolemia. According to combination theory N. N. Anichkova, in the development of atherosclerosis, in addition to the nutritional factor, endogenous disorders of lipid metabolism and its regulation, mechanical effects on the vessel wall, changes in blood pressure, mainly its increase, as well as dystrophic changes in the arterial wall itself are important. In this combination of causes and mechanisms of atherogenesis, some (nutritional and/or endogenous hypercholesterolemia) play the role of an initial factor. Others either provide an increased supply of cholesterol into the vessel wall or reduce its excretion from it through the lymphatic vessels.
In the blood, cholesterol is contained in chylomicrons (fine particles not dissolved in plasma) and lipoproteins - supramolecular heterogeneous complexes of triglycerides, cholesterol esters (core), phospholipids, cholesterol and specific proteins (apoproteins: APO A, B, C, E), forming surface layer. There are certain differences between lipoproteins in size, core-to-shell ratio, qualitative composition and atherogenicity.
Four main fractions of blood plasma lipoproteins have been identified depending on density and electrophoretic mobility.
Noteworthy is the high protein content and low lipid content in the fraction of high-density lipoproteins (HDL - α-lipoproteins) and, conversely, the low protein content and high - lipid content in the fractions of chylomicrons, very low-density lipoproteins (VLDL - pre-β-lipoproteins ) and low-density lipoproteins (LDL - β-lipoproteins).
Thus, blood plasma lipoproteins deliver cholesterol and triglycerides synthesized and obtained from food to the places of their use and storage.
HDL has an antiatherogenic effect by reverse transport of cholesterol from cells, including from blood vessels, to the liver with subsequent excretion from the body in the form of bile acids. The remaining fractions of lipoproteins (especially LDL) are atherogenic, causing excessive accumulation of cholesterol in the vascular wall.
IN table 5 The classification of primary (genetically determined) and secondary (acquired) hyperlipoproteinemia with varying degrees of severity of atherogenic action is given. As follows from the table, the main role in the development of atheromatous changes in blood vessels is played by LDL and VLDL, their increased concentration in the blood, and excessive entry into the vascular intima.
Excessive transport of LDL and VLDL into the vascular wall results in damage to the endothelium.
In accordance with the concept of American researchers I. Goldstein and M. Brown, LDL and VLDL enter cells by interacting with specific receptors (APO B, E-glycoprotein receptors), after which they are endocytically captured and fused with lysosomes. In this case, LDL is broken down into proteins and cholesterol esters. Proteins are broken down into free amino acids, which leave the cell. Cholesterol esters undergo hydrolysis to form free cholesterol, which enters the cytoplasm from lysosomes and is subsequently used for various purposes (membrane formation, synthesis of steroid hormones, etc.). It is important that this cholesterol inhibits its synthesis from endogenous sources, in excess it forms “reserves” in the form of cholesterol esters and fatty acids, but, most importantly, through a feedback mechanism it inhibits the synthesis of new receptors for atherogenic lipoproteins and their further entry into the cell. Along with the regulated receptor-mediated mechanism of LP transport, which ensures the internal needs of cells for cholesterol, interendothelial transport is described, as well as the so-called unregulated endocytosis, which is transcellular, including transendothelial vesicular transport of LDL and VLDL with subsequent exocytosis (into the intima of arteries from the endothelium, macrophages, smooth muscle cells).
Taking into account the stated ideas mechanism of the initial stage of atherosclerosis, characterized by excessive accumulation of lipids in the intima of the arteries, may be caused by:
1. Genetic anomaly of receptor-mediated endocytosis of LDL (absence of receptors - less than 2% of the norm, a decrease in their number - 2 - 30% of the norm). The presence of such defects was found in familial hypercholesterolemia (type II A hyperbetalipoproteinemia) in homo- and heterozygotes. A line of rabbits (Watanabe) with a hereditary defect in LDL receptors was bred.
2. Overload of receptor-mediated endocytosis in alimentary hypercholesterolemia. In both cases, there is a sharp increase in the unregulated endocytotic uptake of drug particles by endothelial cells, macrophages and smooth muscle cells of the vascular wall due to severe hypercholesterolemia.
3. Slowing down the removal of atherogenic lipoproteins from the vascular wall through the lymphatic system due to hyperplasia, hypertension, and inflammatory changes.
A significant additional point is the various transformations (modifications) of lipoproteins in the blood and vascular wall. We are talking about the formation under conditions of hypercholesterolemia of autoimmune complexes of LP - IgG in the blood, soluble and insoluble complexes of LP with glycosaminoglycans, fibronectin, collagen and elastin in the vascular wall (A. N. Klimov, V. A. Nagornev).
Compared with native drugs, the uptake of modified drugs by intimal cells, primarily macrophages (via cholesterol-unregulated receptors), increases sharply. This is believed to be the reason for the transformation of macrophages into so-called foam cells, which form the morphological basis lipid stain stages and with further progression - atherom. The migration of blood macrophages into the intima is ensured by the monocyte chemotactic factor, formed under the influence of LP and interleukin-1, which is released from the monocytes themselves.
At the final stage, they are formed fibrous plaques as a response of smooth muscle cells, fibroblasts and macrophages to damage, stimulated by growth factors of platelets, endothelial cells and smooth muscle cells, as well as the stage of complicated lesions - calcification, thrombus formation etc. ( rice. 19.13).
The above concepts of the pathogenesis of atherosclerosis have their strengths and weaknesses. The most valuable advantage of the concept of general metabolic disorders in the body and primary lipoidosis of the arterial wall is the presence of an experimental cholesterol model. The concept of the primary significance of local changes in the arterial wall, despite the fact that it was expressed more than 100 years ago, does not yet have a convincing experimental model.
As can be seen from the above, in general they can complement each other.
Let us especially consider the problem of modeling atherosclerosis. The experimental model of the latter is revealing in many respects.
The rabbit, a herbivore, is introduced into the gastrointestinal tract over a long period of time with a huge amount of cholesterol, i.e., a food product that is actually alien to it. But throughout human history, foods containing cholesterol have been normal dietary ingredients. The enormous importance of cholesterol for the diverse functions of the body is also reflected in the ability of the latter to synthesize cholesterol regardless of diet; the place of synthesis is, in particular, the arterial system, i.e., the walls of the arteries.
Alien food product for rabbits- cholesterol - floods the blood and, as a foreign chemical body, which does not have adequate enzyme systems in the rabbit’s body that break down cholesterol, or organs capable of releasing cholesterol into the external environment, is deposited in abundance in the reticuloendothelial system and in the arterial system, passing its endothelial barrier. This is the general fate of large-molecular compounds (such as methylcellulose, pectin, polyvinyl alcohol), which are not broken down by the body’s means and are not released by it.
Consequently, from a general theoretical standpoint that determines the essence of any model, the phenomenon obtained in rabbits has only an external resemblance to human arteriosclerosis. This similarity is morphological, chemical, but not etiological (ecological) and not pathogenetic.
The rabbit model of atherosclerosis is primarily the result of inadequate nutrition. It cannot, therefore, be considered as a model of human atherosclerosis and as a model of metabolic disorders of cholesterol metabolism, if only because deposits of foreign substances cannot be documentation of metabolic disorders of the same substances, just as, for example, lead deposits in bones do not document lead disorders exchange.
And the last thing: in human atherosclerosis, the issue of cholesterol metabolism disorders is resolved rather negatively.
The foregoing does not exclude the great cognitive significance of the same model.
The latter teaches that vascular barriers- a very conditional concept and that large molecular compounds can freely pass through them even outside of special dysoria, i.e. such forms of permeability of the vascular walls that occur during edema and inflammation. The model also emphasizes the importance of the arterial system in capturing all circulating chemical compounds that are generally foreign to the body or that have become so in the process, for example, of denaturation of protein bodies (amyloidosis, hyalinosis).
A methodologically important aspect of the same model is that it reveals the danger of one-sided judgments, in this case based on purely morphological documentation.
“The problem of causality in medicine”, I.V. Davydovsky
The history of experimental disease modeling is instructive in many respects, primarily for resolving fundamental issues related to etiology. It is also instructive in terms of the general methodology of biological experiment, its theoretical foundations and practical conclusions from it. It is necessary to be aware that every model is a known simplification, only a more or less clear copy of the original, some kind of...
Every experience is a “violent test of nature” (I. Muller, Muller), of its laws. “Nature itself does not violate its laws” (Leonardo Da Vinci). However, every experiment, every modeling (of infection, cancer, hypertension, etc.) is inevitably associated with some kind of violation of laws and often with distortion of the latter, since the law is not yet known to the experimenter and the corresponding searches are sometimes based on...
There seems to be no such thing as an absolutely decisive experiment, especially in biology, where there are so many unknown quantities that it is difficult to set up a reliably controlled experiment. If we are talking about a theory, then experiment “cannot fully and finally confirm” it because “the same result can follow from different theories.” With the greatest and yet not absolute accuracy, an experiment can...
The experiment must be based on the practice of observation and on the theoretical constructions that this practice gives rise to. In other words, first observation, then generalizing thoughts and ideas arising from observations, and finally modeling. Consequently, the “need for experiment” follows from practical experience, when ideas and questions arise as a starting point for experience (S. P. Botkin). The experimental method itself...
Artificially injecting pneumococci into a rabbit and causing it to develop pneumonia formally speaks of pneumococcus as the cause of the infection. However, it is well known that pneumonia usually occurs spontaneously, that is, autoinfection, without any exogenous infection. It is obvious that the conclusion made about pneumococcus as the cause or “main cause” of pneumonia is only suitable for the specified experimental setup, i.e. for this...
The original meaning of the concept "atherosclerosis", proposed by Marchand in 1904, came down to only two types of changes: the accumulation of fatty substances in the form of mushy masses in the inner lining of the arteries (from the Greek athere - porridge) and sclerosis itself - a connective tissue thickening of the artery wall (from the Greek scleras - hard). The modern interpretation of atherosclerosis is much broader and includes ... “various combinations of changes in the intima of the arteries, manifested in the form of focal deposition of lipids, complex carbohydrate compounds, blood elements and products circulating in it, the formation of connective tissue and calcium deposition” (WHO definition).
Sclerotic vessels (the most common location is the aorta, arteries of the heart, brain, lower extremities) are characterized by increased density and fragility. Due to a decrease in elastic properties, they are not able to adequately change their lumen depending on the need of an organ or tissue for blood supply.
Initially, the functional inferiority of sclerotically altered vessels, and therefore organs and tissues, is detected only when increased demands are placed on them, i.e., when the load increases. Further progression of the atherosclerotic process can lead to decreased performance at rest.
A strong degree of atherosclerotic process is usually accompanied by narrowing and even complete closure of the lumen of the arteries. With the slow sclerosis of arteries in organs with impaired blood supply, atrophic changes occur with the gradual replacement of functionally active parenchyma by connective tissue.
Rapid narrowing or complete closure of the lumen of the artery (in the case of thrombosis, thromboembolism or hemorrhage into the plaque) leads to necrosis of the organ area with impaired blood circulation, i.e. to a heart attack. Myocardial infarction is the most common and most dangerous complication of atherosclerosis of the coronary arteries.
Experimental models. In 1912, N. N. Anichkov and S. S. Khalatov proposed a method for modeling atherosclerosis in rabbits by introducing cholesterol inside (through a tube or by mixing it with regular food). Pronounced atherosclerotic changes developed after several months with daily use of 0.5 - 0.1 g of cholesterol per 1 kg of body weight. As a rule, they were accompanied by an increase in the level of cholesterol in the blood serum (3-5 times compared to the initial level), which was the basis for the assumption of a leading pathogenetic role in the development of atherosclerosis hypercholesterolemia. This model is easily reproducible not only in rabbits, but also in chickens, pigeons, monkeys, and pigs.
In dogs and rats resistant to cholesterol, atherosclerosis is reproduced by the combined effect of cholesterol and methylthiouracil, which suppresses thyroid function. This combination of two factors (exogenous and endogenous) leads to prolonged and severe hypercholesterolemia (over 26 mmol/l - 100 mg%). Adding butter and bile salts to food also contributes to the development of atherosclerosis.
In chickens (roosters), experimental atherosclerosis of the aorta develops after long-term (4 - 5 months) exposure to diethylstilbestrol. In this case, atherosclerotic changes appear against the background of endogenous hypercholesterolemia, resulting from a violation of the hormonal regulation of metabolism.
Etiology. The given experimental examples, as well as observations of spontaneous human atherosclerosis and its epidemiology, indicate that this pathological process develops as a result of the combined action of a number of factors (environmental, genetic, nutritional). In each individual case, one of them comes to the fore. There are factors that cause atherosclerosis and factors that contribute to its development.
On rice. 19.12 a list of the main etiological factors (risk factors) of atherogenesis is given. Some of them (heredity, gender, age) are endogenous. They manifest their effect from the moment of birth (gender, heredity) or at a certain stage of postnatal ontogenesis (age). Other factors are exogenous. The human body encounters their effects at various age periods.
The role of hereditary factors The occurrence of atherosclerosis is confirmed by statistical data on the high incidence of coronary heart disease in individual families, as well as in identical twins. We are talking about hereditary forms of hyperlipoproteinemia, genetic abnormalities of cellular receptors for lipoproteins.
Floor. At the age of 40 - 80 years, men suffer from atherosclerosis and myocardial infarction of an atherosclerotic nature more often than women (on average 3 - 4 times). After 70 years, the incidence of atherosclerosis among men and women is approximately the same. This indicates that the incidence of atherosclerosis among women occurs at a later period. These differences are associated, on the one hand, with a lower initial level of cholesterol and its content mainly in the fraction of non-atherogenic a-lipoproteins in the blood serum of women, and on the other, with the anti-sclerotic effect of female sex hormones. A decrease in the function of the gonads due to age or for any other reason (removal of the ovaries, their irradiation) causes an increase in serum cholesterol levels and a sharp progression of atherosclerosis.
It is assumed that the protective effect of estrogens is reduced not only to the regulation of cholesterol in the blood serum, but also other types of metabolism in the arterial wall, in particular oxidative. This anti-sclerotic effect of estrogens manifests itself mainly in relation to the coronary vessels.
Age. A sharp increase in the frequency and severity of atherosclerotic vascular lesions due to age, especially noticeable after 30 years (see. rice. 19.12), gave rise to some researchers the idea that atherosclerosis is a function of age and is an exclusively biological problem [Davydovsky I.V., 1966]. This explains the pessimistic attitude towards a practical solution to the problem in the future. Most researchers, however, are of the opinion that age-related and atherosclerotic changes in blood vessels are various forms of arteriosclerosis, especially in the later stages of their development, but age-related changes in blood vessels contribute to its development. The effect of age, which promotes atherosclerosis, manifests itself in the form of local structural, physicochemical and biochemical changes in the arterial wall and general metabolic disorders (hyperlipemia, hyperlipoproteinemia, hypercholesterolemia) and its regulation.
Excessive nutrition. Experimental studies by N. N. Anichkov and S. S. Khalatov suggested the importance of the etiological role in the occurrence of spontaneous atherosclerosis of excess nutrition, in particular, excess intake of dietary fats. The experience of countries with a high standard of living convincingly proves that the more energy needs are met through animal fats and cholesterol-containing foods, the higher the cholesterol level in the blood and the incidence of atherosclerosis. On the contrary, in countries where animal fats account for a small part of the energy value of the daily diet (about 10%), the incidence of atherosclerosis is low (Japan, China).
In accordance with the program developed in the USA, based on these facts, reducing fat intake from 40% of total calories to 30% by the year 2000 should reduce mortality from myocardial infarction by 20 - 25%.
Stress. The incidence of atherosclerosis is higher among people in “stressful professions,” i.e. professions that require prolonged and strong nervous tension (doctors, teachers, lecturers, administrative staff, pilots, etc.).
In general, the incidence of atherosclerosis is higher among the urban population compared to the rural population. This can be explained by the fact that in a big city a person is more often exposed to neurogenic stress influences. Experiments confirm the possible role of neuropsychic stress in the occurrence of atherosclerosis. The combination of a high-fat diet with nervous tension should be considered unfavorable.
Physical inactivity. A sedentary lifestyle and a sharp decrease in physical activity (hypodynamia), characteristic of humans in the second half of the 20th century, are another important factor in atherogenesis. This position is supported by the lower incidence of atherosclerosis among manual workers and the higher incidence among people engaged in mental work; faster normalization of cholesterol levels in the blood serum after its excess intake from the outside under the influence of physical activity.
The experiment revealed pronounced atherosclerotic changes in the arteries of rabbits after placing them in special cages, which significantly reduced their motor activity. A combination of a sedentary lifestyle and excess nutrition poses a particular atherogenic danger.
Intoxication. The influence of alcohol, nicotine, intoxication of bacterial origin and intoxication caused by various chemicals (fluorides, CO, H 2 S, lead, benzene, mercury compounds) are also factors contributing to the development of atherosclerosis. In most of the intoxications examined, not only general disorders of fat metabolism characteristic of atherosclerosis were noted, but also typical dystrophic and infiltrative-proliferative changes in the arterial wall.
Arterial hypertension Apparently, it does not have independent significance as a risk factor. This is evidenced by the experience of countries (Japan, China), whose population often suffers from hypertension and rarely from atherosclerosis. However, high blood pressure is becoming a contributing factor to the development of atherosclerosis.
factor in combination with others, especially if it exceeds 160/90 mm Hg. Art. Thus, with the same cholesterol level, the incidence of myocardial infarction with hypertension is five times higher than with normal blood pressure. In an experiment on rabbits whose food was supplemented with cholesterol, atherosclerotic changes develop faster and reach a greater extent against the background of hypertension.
Hormonal disorders, metabolic diseases. In some cases, atherosclerosis occurs against the background of previous hormonal disorders (diabetes mellitus, myxedema, decreased function of the gonads) or metabolic diseases (gout, obesity, xanthomatosis, hereditary forms of hyperlipoproteinemia and hypercholesterolemia). The etiological role of hormonal disorders in the development of atherosclerosis is also evidenced by the above experiments on the experimental reproduction of this pathology in animals by influencing the endocrine glands.
Pathogenesis. Existing theories of the pathogenesis of atherosclerosis can be reduced to two, fundamentally different in their answers to the question: what is primary and what is secondary in atherosclerosis, in other words, what is the cause and what is the consequence - lipoidosis of the inner lining of the arteries or degenerative-proliferative changes in the latter. This question was first raised by R. Virchow (1856). He was the first to answer it, pointing out that “under all conditions, the process probably begins with a certain loosening of the connective tissue basic substance, of which the inner layer of the arteries mostly consists.”
Since then, the idea of the German school of pathologists and its followers in other countries began, according to which, with atherosclerosis, dystrophic changes in the inner lining of the artery wall initially develop, and the deposition of lipids and calcium salts is a secondary phenomenon. The advantage of this concept is that it is able to explain the development of spontaneous and experimental atherosclerosis both in cases where there are pronounced disorders of cholesterol metabolism, and in their absence. The authors of this concept assign a primary role to the arterial wall, i.e., the substrate that is directly involved in the pathological process. “Atherosclerosis is not only and not so much a reflection of general metabolic changes (in the laboratory they can even be elusive), but rather a derivative of the own structural, physical and chemical transformations of the substrate of the arterial wall... The primary factor leading to atherosclerosis lies precisely in the arterial wall itself , in its structure and in its enzyme system" [Davydovsky I.V., 1966].
In contrast to these views, since the experiments of N.N. Anichkov and S.S. Khalatov, mainly thanks to the research of domestic and American authors, the concept of the role in the development of atherosclerosis of general metabolic disorders in the body, accompanied by hypercholesterolemia, hyper- and dyslipoproteinemia, has been successfully developed. From this point of view, atherosclerosis is a consequence of the primary diffuse infiltration of lipids, in particular cholesterol, into the unchanged inner lining of the arteries. Further changes in the vascular wall (the phenomena of mucoid edema, dystrophic changes in the fibrous structures and cellular elements of the subendothelial layer, productive changes) develop due to the presence of lipids in it, i.e. they are secondary.
Initially, the leading role in increasing the level of lipids, especially cholesterol, in the blood was attributed to the nutritional factor (excessive nutrition), which gave the name to the corresponding theory of the occurrence of atherosclerosis - nutritional. However, very soon it had to be supplemented, since it became obvious that not all cases of atherosclerosis can be put in a causal relationship with nutritional hypercholesterolemia. According to combination theory N. N. Anichkova, in the development of atherosclerosis, in addition to the nutritional factor, endogenous disorders of lipid metabolism and its regulation, mechanical effects on the vessel wall, changes in blood pressure, mainly its increase, as well as dystrophic changes in the arterial wall itself are important. In this combination of causes and mechanisms of atherogenesis, some (nutritional and/or endogenous hypercholesterolemia) play the role of an initial factor. Others either provide an increased supply of cholesterol into the vessel wall or reduce its excretion from it through the lymphatic vessels.
In the blood, cholesterol is contained in chylomicrons (fine particles not dissolved in plasma) and lipoproteins - supramolecular heterogeneous complexes of triglycerides, cholesterol esters (core), phospholipids, cholesterol and specific proteins (apoproteins: APO A, B, C, E), forming surface layer. There are certain differences between lipoproteins in size, core-to-shell ratio, qualitative composition and atherogenicity.
Four main fractions of blood plasma lipoproteins have been identified depending on density and electrophoretic mobility.
Noteworthy is the high protein content and low lipid content in the fraction of high-density lipoproteins (HDL - α-lipoproteins) and, conversely, the low protein content and high - lipid content in the fractions of chylomicrons, very low-density lipoproteins (VLDL - pre-β-lipoproteins ) and low-density lipoproteins (LDL - β-lipoproteins).
Thus, blood plasma lipoproteins deliver cholesterol and triglycerides synthesized and obtained from food to the places of their use and storage.
HDL has an antiatherogenic effect by reverse transport of cholesterol from cells, including from blood vessels, to the liver with subsequent excretion from the body in the form of bile acids. The remaining fractions of lipoproteins (especially LDL) are atherogenic, causing excessive accumulation of cholesterol in the vascular wall.
IN table 5 The classification of primary (genetically determined) and secondary (acquired) hyperlipoproteinemia with varying degrees of severity of atherogenic action is given. As follows from the table, the main role in the development of atheromatous changes in blood vessels is played by LDL and VLDL, their increased concentration in the blood, and excessive entry into the vascular intima.
Excessive transport of LDL and VLDL into the vascular wall results in damage to the endothelium.
In accordance with the concept of American researchers I. Goldstein and M. Brown, LDL and VLDL enter cells by interacting with specific receptors (APO B, E-glycoprotein receptors), after which they are endocytically captured and fused with lysosomes. In this case, LDL is broken down into proteins and cholesterol esters. Proteins are broken down into free amino acids, which leave the cell. Cholesterol esters undergo hydrolysis to form free cholesterol, which enters the cytoplasm from lysosomes and is subsequently used for various purposes (membrane formation, synthesis of steroid hormones, etc.). It is important that this cholesterol inhibits its synthesis from endogenous sources, in excess it forms “reserves” in the form of cholesterol esters and fatty acids, but, most importantly, through a feedback mechanism it inhibits the synthesis of new receptors for atherogenic lipoproteins and their further entry into the cell. Along with the regulated receptor-mediated mechanism of LP transport, which ensures the internal needs of cells for cholesterol, interendothelial transport is described, as well as the so-called unregulated endocytosis, which is transcellular, including transendothelial vesicular transport of LDL and VLDL with subsequent exocytosis (into the intima of arteries from the endothelium, macrophages, smooth muscle cells).
Taking into account the stated ideas mechanism of the initial stage of atherosclerosis, characterized by excessive accumulation of lipids in the intima of the arteries, may be caused by:
1. Genetic anomaly of receptor-mediated endocytosis of LDL (absence of receptors - less than 2% of the norm, a decrease in their number - 2 - 30% of the norm). The presence of such defects was found in familial hypercholesterolemia (type II A hyperbetalipoproteinemia) in homo- and heterozygotes. A line of rabbits (Watanabe) with a hereditary defect in LDL receptors was bred.
2. Overload of receptor-mediated endocytosis in alimentary hypercholesterolemia. In both cases, there is a sharp increase in the unregulated endocytotic uptake of drug particles by endothelial cells, macrophages and smooth muscle cells of the vascular wall due to severe hypercholesterolemia.
3. Slowing down the removal of atherogenic lipoproteins from the vascular wall through the lymphatic system due to hyperplasia, hypertension, and inflammatory changes.
A significant additional point is the various transformations (modifications) of lipoproteins in the blood and vascular wall. We are talking about the formation under conditions of hypercholesterolemia of autoimmune complexes of LP - IgG in the blood, soluble and insoluble complexes of LP with glycosaminoglycans, fibronectin, collagen and elastin in the vascular wall (A. N. Klimov, V. A. Nagornev).
Compared with native drugs, the uptake of modified drugs by intimal cells, primarily macrophages (via cholesterol-unregulated receptors), increases sharply. This is believed to be the reason for the transformation of macrophages into so-called foam cells, which form the morphological basis lipid stain stages and with further progression - atherom. The migration of blood macrophages into the intima is ensured by the monocyte chemotactic factor, formed under the influence of LP and interleukin-1, which is released from the monocytes themselves.
At the final stage, they are formed fibrous plaques as a response of smooth muscle cells, fibroblasts and macrophages to damage, stimulated by growth factors of platelets, endothelial cells and smooth muscle cells, as well as the stage of complicated lesions - calcification, thrombus formation etc. ( rice. 19.13).
The above concepts of the pathogenesis of atherosclerosis have their strengths and weaknesses. The most valuable advantage of the concept of general metabolic disorders in the body and primary lipoidosis of the arterial wall is the presence of an experimental cholesterol model. The concept of the primary significance of local changes in the arterial wall, despite the fact that it was expressed more than 100 years ago, does not yet have a convincing experimental model.
As can be seen from the above, in general they can complement each other.
