Skip to main content
Log in

Analysis of inflammatory processes in diffuse thickening of human aorta intima

  • Published:
Cell and Tissue Biology Aims and scope Submit manuscript

Abstract

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Similar content being viewed by others

Abbreviations

DIT:

diffuse intima thickening

HLA-DR:

class II major histocompatibility complex molecules (human leucocyte antigen)

References

  • 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.

    Article  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • Berliner, J.A. and Watson, A.D., A role for oxidized phospholipids in atherosclerosis, N. Engl. J. Med., 2005, vol. 353, pp. 9–11.

    Article  PubMed  CAS  Google Scholar 

  • Bobryshev, Y.V., Dendritic cells in atherosclerosis: current status of the problem and clinical relevance, Eur. Heart J., 2005, vol. 26, pp. 1700–1704.

    Article  PubMed  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • Galkina, E. and Ley, K., Leukocyte influx in atherosclerosis, Curr. Drug Targets, 2007, vol. 8, pp. 1239–1248.

    Article  PubMed  CAS  Google Scholar 

  • 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 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • Hansson, G.K., Atherosclerosis-an immune disease: the Anitschkov lecture 2007, Atherosclerosis, 2009, vol. 202, pp. 2–10.

    Article  PubMed  CAS  Google Scholar 

  • Hansson, G.K. and Hermansson, A., The immune system in atherosclerosis, Nat. Immunol., 2011, vol. 12, pp. 204–212.

    Article  PubMed  CAS  Google Scholar 

  • Jores L., Herz, Gefasse, Handbuch der speziellen pathologischen Anatomie und Histologie, Berlin: Springer: 1924.

    Google Scholar 

  • Katsuda, S. and Kaji, T., Atherosclerosis and extracellular matrix, Atheroscler. Thromb., 2003, vol. 10, pp. 267–274.

    Article  CAS  Google Scholar 

  • Klingenberg, R. and Hansson, G.K., Treating inflammation in atherosclerotic cardiovascular disease: emerging therapies, Eur. Heart J., 2009, vol. 30, pp. 2838–2344.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    PubMed  CAS  Google Scholar 

  • Montecucco, F. and Mach, F., Update on statin-mediated anti-inflammatory activities in atherosclerosis, Semin. Immunopathol., 2009, vol. 31, pp. 127–42.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    PubMed  CAS  Google Scholar 

  • 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 

  • 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.

    PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • Pearse, A.G., Histochemistry: Theoretical and Applied, London: Churchill Ltd., 1969.

    Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    PubMed  CAS  Google Scholar 

  • Ross, R., Atherosclerosis—an inflammatory disease, N. Engl. J. Med., 1999, vol. 340, pp. 115–126.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • Seyama, Y. and Wachi, H., Atherosclerosis and matrix dystrophy, Atheroscler. Thromb., 2004, vol. 11, pp. 236–245.

    Article  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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 

  • 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.

    CAS  Google Scholar 

  • 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.

    Article  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • Wick, G., Knoflach, M., and Xu, Q., Autoimmune and inflammatory mechanisms in atherosclerosis, Annu. Rev. Immunol., 2004, vol. 22, pp. 361–403.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    PubMed  CAS  Google Scholar 

  • Willens, S.L., The nature of diffuse intimal thickening of arteries, Am. J. Pathol., 1951, vol. 27, pp. 825–833.

    Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to V. P. Karagodin.

Additional information

Original Russian Text © Y.V. Bobryshev, V.P. Karagodin, M.M. Moisenovich, A.A. Melnichenko, A.N. Orekhov, 2013, published in Tsitologiya, 2013, Vol. 55, No. 6, pp. 394–405.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Bobryshev, Y.V., Karagodin, V.P., Moisenovich, M.M. et al. Analysis of inflammatory processes in diffuse thickening of human aorta intima. Cell Tiss. Biol. 7, 439–449 (2013). https://doi.org/10.1134/S1990519X13050039

Download citation

  • Received:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1134/S1990519X13050039

Keywords

Navigation