Cell and Tissue Biology

, Volume 7, Issue 5, pp 439–449 | Cite as

Analysis of inflammatory processes in diffuse thickening of human aorta intima

  • Y. V. Bobryshev
  • V. P. Karagodin
  • M. M. Moisenovich
  • A. A. Melnichenko
  • A. N. Orekhov


It is generally recognized that accumulation of lipids and immune inflammatory cells is an early sign of atherosclerosis. In the present study, we investigated the relationship between the deposition of lipids, immune inflammatory cell content and expression of HLA-DR molecules, and class II major histocompatibility complex (MHC) (a marker of immune activation) in diffuse intima thickening (DIT). Lipids, including triglycerides, cholesterol esters, free cholesterol, and phospholipids were studied by chromatography and Oil Red O histochemistry, as well as by electron microscopy. Immune inflammatory cells and the expression of HLA-DR were investigated by immunohistochemistry in serial sections of the same tissue samples. It has been shown that the lipids were unevenly distributed in DIT. In the juxtaluminal sublayer, lipids were detected in the cytoplasm of intima cells and the extracellular area. In the juxtamedial musculoelastic sublayer of the intima, lipids were present predominantly along elastic fibers. The positive correlation between the presence of lipids and the expression of HLA-DR was revealed (r = 0.79; p < 0.001). A positive correlation was also found between the deposition of lipids and the number of immune inflammatory cells, although correlation was different for different sublayers of the intima. In particular, the correlation between the deposition of lipids and immune inflammatory cells in the juxtaluminal sublayer of the intima was higher (r = 0.69; p < 0.001) than in the juxtamedial musculoelastic layer (r = 0.28; p < 0.001). These data support the hypothesis that the accumulation of lipids in the intima is a key factor in the initiation of inflammatory reactions. At the preatherosclerotic stage of development of this disease, earlier pathological processes associated with lipid-dependent activation of immune cells occur mainly in the juxtaluminal portion of the intima.


aorta intima immune inflammation lipids HLA-DR 



diffuse intima thickening


class II major histocompatibility complex molecules (human leucocyte antigen)


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Andreeva, E.R., Orekhov, A.N., and Smirnov, V.N., Quantitative estimation of lipidladen cells in atherosclerotic lesions of the human aorta, Acta Anat. (Basel), 1991, vol. 141, pp. 316–323.CrossRefGoogle Scholar
  2. Andreeva, E.R., Pugach, I.M., Gordon, D., and Orekhov, A.N., Continuous subendothelial network formed by pericyte-like cells in human vascular bed, Tissue Cell, 1998, vol. 30, pp. 127–135.PubMedCrossRefGoogle Scholar
  3. Andreeva, E.R., Pugach, I.M., and Orekhov, A.N., Collagen-synthesizing cells in initial and advanced atherosclerotic lesions of human aorta, Atherosclerosis, 1997, vol. 130, pp. 133–142.PubMedCrossRefGoogle Scholar
  4. Anichkow, N.N., Vessels, in: Handbook on Particular Human Anatomy and Pathology, Part II: Heart and Vessels, Moscow: Medgiz, 1947, pp. 262–558.Google Scholar
  5. Babaev, V.R., Bobryshev, Y.V., Sukhova, G.K., and Kasantseva, I.A., Monocyte/macrophage accumulation and smooth muscle cell phenotypes in early atherosclerotic lesions of human aorta, Atherosclerosis, 1993, vol. 100, pp. 237–248.PubMedCrossRefGoogle Scholar
  6. Bentzon, J.F. and Falk, E., Atherosclerotic lesions in mouse and man: is it the same disease Curr. Opin. Lipidol., 2010, vol. 21, pp. 434–440.PubMedCrossRefGoogle Scholar
  7. Berliner, J.A. and Watson, A.D., A role for oxidized phospholipids in atherosclerosis, N. Engl. J. Med., 2005, vol. 353, pp. 9–11.PubMedCrossRefGoogle Scholar
  8. Bobryshev, Y.V., Dendritic cells in atherosclerosis: current status of the problem and clinical relevance, Eur. Heart J., 2005, vol. 26, pp. 1700–1704.PubMedCrossRefGoogle Scholar
  9. Bobryshev, Y.V. and Lord, R.S., Ultrastructural recognition of cells with dendritic cell morphology in human aortic intima. Contacting interactions of vascular dendritic cells in athero-resistant and athero-prone areas of the normal aorta, Arch. Histol. Cytol., 1995, vol. 58, pp. 307–322.PubMedCrossRefGoogle Scholar
  10. Bobryshev, Y.V. and Lord, R.S., Langhans cells of human arterial intima: uniform by stellate appearance but different by nature, Tissue Cell, 1996, vol. 28, pp. 177–194.PubMedCrossRefGoogle Scholar
  11. Bobryshev, Y.V. and Lord, R.S., Mapping of vascular dendritic cells in atherosclerotic arteries suggests their involvement in local immune-inflammatory reactions, Cardiovasc. Res., 1998, vol. 37, pp. 799–810.PubMedCrossRefGoogle Scholar
  12. Bobryshev, Y.V. and Lord, R.S., Accumulation of co-localized unesterified cholesterol and neutral lipids within vacuolised elastin fibres in athero-prone areas of the human aorta, Atherosclerosis, 1999, vol. 142, pp. 121–131.PubMedCrossRefGoogle Scholar
  13. Bobryshev, Y.V. and Lord, R.S., Expression of heat shock protein-70 by dendritic cells in the arterial intima and its potential significance in atherogenesis, Vasc. Surg., 2002, vol. 35, pp. 368–375.CrossRefGoogle Scholar
  14. Bobryshev, Y.V., Lord, R.S., and Warren, B.A., Calcified deposit formation in intimal thickenings of the human aorta, Atherosclerosis, 1995, vol. 118, pp. 9–21.PubMedCrossRefGoogle Scholar
  15. Bobryshev, Y.V., Moisenovich, M.M., Pustovalova, O.L., Agapov, I.I., and Orekhov, A.N., Widespread distribution of HLA-DR-expressing cells in macroscopically undiseased intima of the human aorta: a possible role in surveillance and maintenance of vascular homeostasis, Immunobiology, 2012, vol. 217, pp. 558–568.PubMedCrossRefGoogle Scholar
  16. Bobryshev, Y.V. and Watanabe, T., Ultrastructural evidence for association of vascular dendritic cells with t-lymphocytes and with B-cells in human atherosclerosis, J. Submicrosc. Cytol. Pathol., 1997, vol. 29, pp. 209–221.PubMedGoogle Scholar
  17. Brooke, B.S., Bayes-Genis, A., and Li, D.Y., New insights into elastin and vascular disease, Trends Cardiovasc. Med., 2003, vol. 13, pp. 176–81.PubMedCrossRefGoogle Scholar
  18. Galkina, E. and Ley, K., Leukocyte influx in atherosclerosis, Curr. Drug Targets, 2007, vol. 8, pp. 1239–1248.PubMedCrossRefGoogle Scholar
  19. Geer, J.C., McGill, H.C., Strong, J.P., and Holman, R.L., Electron microscopy of human atherosclerotic lesions, Fed. Proc., 1960, vol. 19, pp. 15–18.Google Scholar
  20. Guyton, J.R., Bocan, T.M., and Schifani, T.A., Quantitative ultrastructural analysis of perifibrous lipid and its association with elastin in nonatherosclerotic human aorta, Arteriosclerosis, 1985, vol. 5, pp. 644–652.PubMedCrossRefGoogle Scholar
  21. Guyton, J.R., and Klemp, K.F., Ultrastructural discrimination of lipid droplets and vesicles in atherosclerosis: value of osmium-thiocarbohydrazide-osmium and tannic acid-paraphenylenediamine techniques, J. Histochem. Cytochem., 1988, vol. 36, pp. 1319–1328.PubMedCrossRefGoogle Scholar
  22. Handunnetthi, L., Ramagopalan, S.V., Ebers, G.C., and Knight, J.C., Regulation of major histocompatibility complex class ii gene expression, genetic variation and disease, Genes Immun., 2010, vol. 11, pp. 99–112.PubMedCrossRefGoogle Scholar
  23. Hansson, G.K., Atherosclerosis-an immune disease: the Anitschkov lecture 2007, Atherosclerosis, 2009, vol. 202, pp. 2–10.PubMedCrossRefGoogle Scholar
  24. Hansson, G.K. and Hermansson, A., The immune system in atherosclerosis, Nat. Immunol., 2011, vol. 12, pp. 204–212.PubMedCrossRefGoogle Scholar
  25. Jores L., Herz, Gefasse, Handbuch der speziellen pathologischen Anatomie und Histologie, Berlin: Springer: 1924.Google Scholar
  26. Katsuda, S. and Kaji, T., Atherosclerosis and extracellular matrix, Atheroscler. Thromb., 2003, vol. 10, pp. 267–274.CrossRefGoogle Scholar
  27. Klingenberg, R. and Hansson, G.K., Treating inflammation in atherosclerotic cardiovascular disease: emerging therapies, Eur. Heart J., 2009, vol. 30, pp. 2838–2344.PubMedCrossRefGoogle Scholar
  28. Kruth, H.S., Localization of unesterified cholesterol in human atherosclerotic lesions. Demonstration of filipinpositive, Oil-Red-O-negative particles, Am. J. Pathol., 1984, vol. 114, pp. 201–208.PubMedGoogle Scholar
  29. Montecucco, F. and Mach, F., Update on statin-mediated anti-inflammatory activities in atherosclerosis, Semin. Immunopathol., 2009, vol. 31, pp. 127–42.PubMedCrossRefGoogle Scholar
  30. Movat, H.Z., More, R.H., and Haust, M.D., The diffuse intimal thickening of the human aorta with aging, Am. J. Pathol., 1958, vol. 34, pp. 1023–1031.PubMedGoogle Scholar
  31. Mukhin, D.N., Orekhov, A.N., Andreeva, E.R., Schindeler, E.M., and Smirnov, V.N., Lipids in cells of atherosclerotic and uninvolved human aorta. III. Lipid distribution in intimal sublayers, Exp. Mol. Pathol., 1991, vol. 54, pp. 22–30.PubMedCrossRefGoogle Scholar
  32. Noma, A., Takahashi, T., and Wada, T., Elastin-lipid Interaction in the Arterial Wall. Part 2. In vitro binding of lipoprotein-lipids to arterial elastin and the inhibitory effect of high density lipoproteins on the process, Atherosclerosis, 1981, vol. 38, pp. 373–382.PubMedCrossRefGoogle Scholar
  33. Orekhov, A.N., Andreeva, E.R., Andrianova, I.V., and Bobryshev, Y.V., Peculiarities of cell composition and cell proliferation in different type atherosclerotic lesions in carotid and coronary arteries, Atherosclerosis, 2010, vol. 212, pp. 436–443.PubMedCrossRefGoogle Scholar
  34. Orekhov, A.N., Andreeva, E.R., Krushinsky, A.V., Novikov, I.D., Tertov, V.V., Nestaiko, G.V., Khashimov, Kh.A., Repin, V.S., and Smirnov, V.N., Intimal cells and atherosclerosis. Relationship between the number of intimal cells and major manifestations of atherosclerosis in the human aorta, Am. J. Pathol., 1986, vol. 125, pp. 402–415.PubMedGoogle Scholar
  35. Orekhov, A.N., Andreeva, E.R., and Tertov, V., The distribution of cells and chemical components in the intima of human aorta, Soc. Med. Rev. A: Cardiol., 1987, vol. 1, pp. 75–100.Google Scholar
  36. Orekhov, A.N., Karpova, I.I., Tertov, V.V., Rudchenko, S.A., Andreeva, E.R., Krushinsky, A.V., and Smirnov, V.N., Cellular composition of atherosclerotic and uninvolved human aortic subendothelial intima. Light-microscopic study of dissociated aortic cells, Am. J. Pathol., 1984, vol. 115, pp. 17–24.PubMedGoogle Scholar
  37. Orekhov, A.N., Tertov, V.V., Novikov, I.D., Krushinsky, A.V., Andreeva, E.R., Lankin, V.Z., and Smirnov, V.N., Lipids in cells of atherosclerotic and uninvolved human aorta. I. Lipid composition of aortic tissue and enzymeisolated and cultured cells, Exp. Mol. Pathol., 1985, vol. 42, pp. 117–137.PubMedCrossRefGoogle Scholar
  38. Pearse, A.G., Histochemistry: Theoretical and Applied, London: Churchill Ltd., 1969.Google Scholar
  39. Poston, R.N., and Hussain, I.F., The immunohistochemical heterogeneity of atheroma macrophages: comparison with lymphoid tissues suggests that recently blood-derived macrophages can be distinguished from longer-resident cells, J. Histochem. Cytochem., 1993, vol. 41, pp. 1503–1512.PubMedCrossRefGoogle Scholar
  40. Rekhter, M.D., Andreeva, E.R., Mironov, A.A., and Orekhov, A.N., Three-dimensional Cytoarchitecture of Normal and Atherosclerotic Intima of Human Aorta, Am. J. Pathol., 1991, vol. 138, pp. 569–580.PubMedGoogle Scholar
  41. Ross, R., Atherosclerosis—an inflammatory disease, N. Engl. J. Med., 1999, vol. 340, pp. 115–126.PubMedCrossRefGoogle Scholar
  42. Schwartz, S.M., deBlois, D., and O’Brien, E.R., The intima: soil for atherosclerosis and restenosis, Circ. Res., 1995, vol. 77, pp. 445–465.PubMedCrossRefGoogle Scholar
  43. Seyama, Y. and Wachi, H., Atherosclerosis and matrix dystrophy, Atheroscler. Thromb., 2004, vol. 11, pp. 236–245.CrossRefGoogle Scholar
  44. Sobenin, I.A, Maksumova, M.A., Slavina, E.S., Balabolkin, M.I., and Orekhov, A.N., Sulfonylureas induce cholesterol accumulation in cultured human intimal cells and macrophages, Atherosclerosis, 1994, vol. 105, pp. 159–163.PubMedCrossRefGoogle Scholar
  45. Stary, H.C., Evolution and progression of atherosclerotic lesions in coronary arteries of children and young adults, Atherosclerosis, 1989, vol. 9, pp. 119–132.Google Scholar
  46. Stary, H.C., Chandler, A.B., Glagov, S., Guyton, J.R., Insull, W., Jr., Rosenfeld, M..E, Schaffer, S.A., Schwartz, C.J., Wagner, W.D., and Wissler, R.W., A definition of initial, fatty streak, and intermediate lesions of atherosclerosis. A report from the Committee on Vascular Lesions of the Council on Arteriosclerosis, American Heart Association, Circulation., 1994, vol. 89, pp. 2462–2478.Google Scholar
  47. Tertov, V.V., Orekhov, A.N., Rudchenko, S.A., Mukhin, D.N., Smirnov, V.N., Molotkovsky, Yu.G., and Bergelson, L.D., Determination of total intracellular lipid content by flow cytofluorometry, Biochem. Biophys. Res. Commun., 1985, vol. 16, pp. 1196–1202.CrossRefGoogle Scholar
  48. Tertov, V.V. and Orekhov, A.N., Metabolism of native and naturally occurring multiple modified low density lipoprotein in smooth muscle cells of human aortic intima, Exp. Mol. Pathol., 1997, vol. 64, pp. 127–145.PubMedCrossRefGoogle Scholar
  49. Tertov, V.V., Sobenin, I.A., Kaplun, V.V., and Orekhov, A.N., Antioxidant content in low density lipoprotein and lipoprotein oxidation in vivo and in vitro, Free Radic. Res., 1998, vol. 29, pp. 165–173.PubMedGoogle Scholar
  50. Thorne, S.A., Abbot, S.E., Stevens, C.R., Winyard, P.G., Mills, P.G., and Blake, D.R., Modified low density lipoprotein and cytokines mediate monocyte adhesion to smooth muscle cells, Atherosclerosis, 1996, vol. 127, pp. 167–176.PubMedCrossRefGoogle Scholar
  51. Vanderlaan, P.A. and Reardon, C.A., Thematic review series: the immune system and atherogenesis. The unusual suspects: an overview of the minor leukocyte populations in atherosclerosis, J. Lipid Res., 2005, vol. 46, pp. 829–838.PubMedCrossRefGoogle Scholar
  52. Velican, C. and Velican, D., Heterogeneity in the composition and aggregation patterns of coronary intima acid mucopolysaccharides (glycosaminoglycans), Atherosclerosis, 1978, vol. 29, pp. 141–159.PubMedCrossRefGoogle Scholar
  53. Velican, C., Velican, D., and Tancu, I., The relationship between intimal necrosis and lipid accumulation during the onset and progression of atherosclerotic lesions, Med. Intern., 1988, vol. 26, pp. 97–107.Google Scholar
  54. Velican, D. and Velican, C., Histochemical study on the glucosaminoglycans (acid mycopolisacharides) of the human coronary arteries, Acta Histochem., 1977, vol. 59, pp. 190–200.PubMedCrossRefGoogle Scholar
  55. Virmani, R., Kolodgie, F.D., Burke, A.P., Farb, A., and Schwartz, S.M., Lessons from sudden coronary death: a comprehensive morphological classification scheme for atherosclerotic lesions, Arterioscler. Thromb. Vasc. Biol., 2000, vol. 20, pp. 1262–1275.PubMedCrossRefGoogle Scholar
  56. Weber, C., Zernecke, A., and Libby, P., The multifaceted contributions of leukocyte subsets to atherosclerosis: lessons from mouse models, Nat. Rev. Immunol., 2008, vol. 8, pp. 802–815.PubMedCrossRefGoogle Scholar
  57. Wick, G., Knoflach, M., and Xu, Q., Autoimmune and inflammatory mechanisms in atherosclerosis, Annu. Rev. Immunol., 2004, vol. 22, pp. 361–403.PubMedCrossRefGoogle Scholar
  58. Wick, G., Romen, M., Amberger, A., Metzler, B., Mayr, M., Falkensammer, G., and Xu, Q., Atherosclerosis, autoimmunity, and vascular-associated lymphoid tissue, FASEB J., 1997, vol. 11, pp. 1199–207.PubMedGoogle Scholar
  59. Willens, S.L., The nature of diffuse intimal thickening of arteries, Am. J. Pathol., 1951, vol. 27, pp. 825–833.Google Scholar

Copyright information

© Pleiades Publishing, Ltd. 2013

Authors and Affiliations

  • Y. V. Bobryshev
    • 1
    • 2
  • V. P. Karagodin
    • 1
  • M. M. Moisenovich
    • 1
  • A. A. Melnichenko
    • 1
  • A. N. Orekhov
    • 1
    • 2
  1. 1.Institute for Atherosclerosis ResearchMoscowRussia
  2. 2.Institute of General Pathology and PathophysiologyMoscowRussia

Personalised recommendations