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Nikolaj Nikolajewitsch Anitschkow (1885–1964) established the cholesterol-fed rabbit as a model for atherosclerosis research

  • Gerald Finking
    Correspondence
    Corresponding author. Present address: Abteilung Innere Medizin II, Medizinische Universitätsklinik und Poliklinik, Robert-Koch-Str. 8, D-89081 Ulm, Germany. Tel.: +49 731 5024384; fax: +49 731 5024442; e-mail: [email protected]
    Affiliations
    Department of Internal Medicine, Division of Experimental Cardiology, University of Ulm, Ulm, Germany
    Search for articles by this author
  • Hartmut Hanke
    Affiliations
    Department of Internal Medicine, Division of Experimental Cardiology, University of Ulm, Ulm, Germany
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      Abstract

      The cholesterol-fed rabbit is a widely used model for experimental atherosclerosis research. In regard to this, one name is periodically mentioned: Nikolaj Nikolajewitsch Anitschkow. Those infrequent reminders of an important name in modern medical history do not pay an adequate tribute to basic findings concerning the pathology and pathogenesis of atherosclerosis. In contrast to research groups at that time conducting experiments with protein enriched diets, Anitschkow demonstrated, in 1913 in St. Petersburg, that it was cholesterol only that caused these atherosclerotic changes in the rabbit arterial intima, which was very similar to human atherosclerosis. By analysing the plaque's development and histology, Anitschkow was able to identify the cell types, on which modern atherosclerosis research is now focussing with a new set of immunohistochemical methods: smooth muscle cells, macrophages and lymphocytes. He noted early (fatty streaks) and advanced (atheromatous plaques) lesions and, by standardizing cholesterol feeding, he discovered that the amount of cholesterol uptake was directly proportional to the degree of atherosclerosis formation. His explanation for this observation was what modern terminology calls `response-to-injury'. With modern immunohistochemical and molecular-biological methods, the cholesterol-fed rabbit can be used to investigate the pathophysiological aspects which also contribute to human atherosclerosis, such as lipoproteins, diabetes, mitogens, growth-factors, adhesion molecules, endothelial-function, receptor-pathways or platelets. This model can be combined with a number of other methods causing endothelial dysfunction and injury, such as balloon denudation, electric stimulation, cuff implantation, artificial hypertension, diabetes or infection. Bred strains of hereditary hypercholesterolemic rabbits or those resistant to a cholesterol-diet provide further possibilities to expand experimental designs.

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      References

        • Anitschkow N
        • Chalatow S
        Ueber experimentelle cholesterinsteatose und ihre bedeutung für die entstehung einiger pathologischer prozesse.
        Centrbl Allg Pathol Pathol Anat. 1913; 24: 1-9
        • Anitschkow N
        Über die veränderungen der kaninchenaorta bei experimenteller cholesterinsteatose.
        Beitr Pathol Anat. 1913; 56: 379-404
        • Bocan TM
        • Mueller SB
        • Mazur MJ
        • Uhlendorf PD
        • Brown EQ
        • Kieft KA
        The relationship between the degree of dietary-induced hypercholesterolemia in the rabbit and atherosclerotic lesion formation.
        Atherosclerosis. 1993; 102: 9-22
        • Constantinides P
        The role of arterial wall injury in atherogenesis and arterial thrombogenesis.
        Zentralbl Pathol Anat. 1989; 135: 517-530
        • Constantinides P
        • Gutmann-Auersperg N
        • Hospes D
        Acceleration of intimal atherogenesis through prior medial injury.
        Arch Pathol. 1958; 66: 247-254
        • Mahley RW
        • Innerarity TL
        • Brown MS
        • Ho YK
        • Goldstein JL
        Cholesteryl ester synthesis in macrophages: stimulation by beta-very low density lipoproteins from cholesterol-fed animals of several species.
        J Lipid Res. 1980; 21: 970
      1. Wissler RW, Vesselinovitch D. Differences Between Human and Animal Atherosclerosis. In: Schettler G, Weizel A, editors. Atherosclerosis. New York: Springer, 1974:319–325.

        • Garbarsch C
        • Matthiesen ME
        • Helin P
        • Lorenzen I
        Spontaneous aortic arteriosclerosis in rabbits of the Danish country strain.
        Atherosclerosis. 1970; 12: 291-300
        • Watanabe T
        • Hirata M
        • Yoshikawa Y
        • Nagafuchi Y
        • Toyoshima H
        Role of macrophages in atherosclerosis. Sequential observations of cholesterol-induced rabbit aortic lesion by the immunoperoxidase technique using monoclonal antimacrophage antibody.
        Lab Invest. 1985; 53: 80-90
        • Adams CW
        • Morgan RS
        Regression of atheroma in the rabbit.
        Atherosclerosis. 1977; 28: 399-404
        • Badimon JJ
        • Badimon L
        • Fuster V
        Regression of atherosclerotic lesions by high density lipoprotein plasma fraction in the cholesterol-fed rabbit.
        J Clin Invest. 1990; 85: 1234-1241
        • Zhu BQ
        • Sievers RE
        • Isenberg WM
        • Smith DL
        • Parmley WW
        Regression of atherosclerosis in cholesterol-fed rabbits: effects of fish oil and verapamil.
        J Am Coll Cardiol. 1990; 15: 231-237
        • Zhu BQ
        • Sievers RE
        • Sun YP
        • Isenberg WM
        • Parmley WW
        Effect of lovastatin on suppression and regression of atherosclerosis in lipid-fed rabbits.
        J Cardiovasc Pharmacol. 1992; 19: 246-255
        • Candipan RC
        • Wang BY
        • Buitrago R
        • Tsao PS
        • Cooke JP
        Regression or progression. Dependency on vascular nitric oxide.
        Arterioscler Thromb Vasc Biol. 1996; 16: 44-50
        • Haarbo J
        • Christiansen C
        The impact of female sex hormones on secondary prevention of atherosclerosis in ovariectomized cholesterol-fed rabbits.
        Atherosclerosis. 1996; 123: 139-144
        • Armstrong ML
        • Warner ED
        • Connor WE
        Regression of coronary atheromatosis in rhesus monkeys.
        Circ Res. 1970; 27: 59-67
        • Superko HR
        • Krauss RM
        Coronary artery disease regression. Convincing evidence for the benefit of aggressive lipoprotein management.
        Circulation. 1994; 90: 1056-1069
        • Gotto Jr, AM
        Lipid lowering and coronary risk.
        Isr J Med Sci. 1996; 32: 355-359
        • Davies MJ
        • Richardson PD
        • Woolf N
        • Katz DR
        • Mann J
        Risk of thrombosis in human atherosclerotic plaques: role of extracellular lipid, macrophage, and smooth muscle cell content.
        Br Heart J. 1993; 69: 377-381
        • Watanabe Y
        Serial inbreeding of rabbits with hereditary hyperlipidemia (WHHL-rabbit).
        Atherosclerosis. 1980; 36: 261-268
        • Goldstein JL
        • Kita T
        • Brown MS
        Defective lipoprotein receptors and atherosclerosis. Lessons from an animal counterpart of familial hypercholesterolemia.
        N Engl J Med. 1983; 309: 288-296
        • Buja LM
        • Kita T
        • Goldstein JL
        • Watanabe Y
        • Brown MS
        Cellular pathology of progressive atherosclerosis in the WHHL rabbit. An animal model of familial hypercholesterolemia.
        Arteriosclerosis. 1983; 3: 87-101
        • Rosenfeld ME
        • Tsukada T
        • Gown AM
        • Ross R
        Fatty streak initiation in Watanabe Heritable Hyperlipemic and comparably hypercholesterolemic fat-fed rabbits.
        Arteriosclerosis. 1987; 7: 9-23
        • Rosenfeld ME
        • Tsukada T
        • Chait A
        • Bierman EL
        • Gown AM
        • Ross R
        Fatty streak expansion and maturation in Watanabe Heritable Hyperlipemic and comparably hypercholesterolemic fat-fed rabbits.
        Arteriosclerosis. 1987; 7: 24-34
        • Rosenfeld ME
        • Ross R
        Macrophage and smooth muscle cell proliferation in atherosclerotic lesions of WHHL and comparably hypercholesterolemic fat-fed rabbits.
        Arteriosclerosis. 1990; 10: 680-687
      2. Esper E, Runge WJ, Gunther R, Buchwald H. Natural history of atherosclerosis and hyperlipidemia in heterozygous WHHL (WHHL-Hh) rabbits. II. Morphologic evaluation of spontaneously occuring aortic and coronary lesions. J Lab Clin Med 1993;103–110.

        • Armstrong ML
        • Heistad DD
        Animal models of atherosclerosis.
        Atherosclerosis. 1990; 85: 15-23
        • Massaro ER
        • Zilversmit DB
        Controlling factors in the maintenance of plasma cholesterol concentration in the rabbit.
        J Nutr. 1977; 107: 596-605
        • Van-Zutphen LF
        • Fox RR
        Strain differences in response to dietary cholesterol by JAX rabbits: correlation with esterase patterns.
        Atherosclerosis. 1977; 28: 435-446
        • Overturf ML
        • Smith SA
        • Hewett-Emmett D
        • Loose-Mitchell DS
        • Soma MR
        • Gotto AMJ
        • Morrisett JD
        Development and partial metabolic characterization of a dietary cholesterol-resistant colony of rabbits.
        J Lipid Res. 1989; 30: 263-273
        • Ross R
        The pathogenesis of atherosclerosis—an update.
        N Engl J Med. 1985; 314: 488-500
        • Stary HC
        • Chandler AB
        • Glagov S
        • Guyton JR
        • Insull Jr, W
        • Rosenfeld ME
        • Schaffer SA
        • Schwartz CJ
        • Wagner WD
        • Wissler RW
        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.
        Arterioscler Thromb. 1994; 14: 840-856
        • McPherson DD
        • Sirna SJ
        • Hiratzka LF
        Coronary arterial remodeling studied by high-frequency epicardial echocardiographie: an early compensatory mechanism in patients with obstructive coronary atherosclerosis.
        J Am Coll Cardiol. 1991; 17: 79-86
        • Gown AM
        • Tsukada T
        • Ross R
        Human atherosclerosis. II. Immunocytochemical analysis of the cellular composition of human atherosclerotic lesions.
        Am J Pathol. 1986; 125: 191-207
        • Tsukada T
        • Rosenfeld M
        • Ross R
        • Gown AM
        Immunocytochemical analysis of cellular components in atherosclerotic lesions. Use of monoclonal antibodies with the Watanabe and fat-fed rabbit.
        Arteriosclerosis. 1986; 6: 601-613
        • Sanders M
        Molecular and cellular concepts in atherosclerosis.
        Pharm Ther. 1994; 61: 109-153
        • Ross R
        The pathogenesis of atherosclerosis: a perspective for the 1990s.
        Nature. 1993; 362: 801-809
        • Stary HC
        • Chandler AB
        • Dinsmore RE
        • Fuster V
        • Glagov S
        • Insull Jr, W
        • Rosenfeld ME
        • Schwartz CJ
        • Wagner WD
        • Wissler RW
        A definition of advanced types of atherosclerotic lesions and a histological classification of atherosclerosis. A report from the Committee on Vascular Lesions of the Council on Arteriosclerosis, American Heart Association.
        Circulation. 1995; 92: 1355-1374
        • Stary HC
        • Blankenhorn DH
        • Chandler AB
        • Glagov S
        • Insull Jr, W
        • Richardson M
        • Rosenfeld ME
        • Schaffer SA
        • Schwartz CJ
        • Wagner WD
        • Wissler RW
        A definition of the intima of human arteries and of its atherosclerosis-prone regions. A report from the Committee on Vascular Lesions of the Council on Arteriosclerosis, American Heart Association.
        Circulation. 1992; 85: 391-405
        • McMillan GC
        • Duff GL
        Mitotic activity in the aortic lesions of experimental cholesterol atherosclerosis of rabbits.
        Arch Pathol. 1948; 46: 179-182
        • Stary HC
        • McMillan GC
        Kinetics of cellular proliferation in experimental atherosclerosis. Radioautography with grain counts in cholesterol-fed rabbits.
        Arch Path. 1970; 89: 173-183
        • Gratzner HG
        Monoclonal antibody to 5-bromo- and 5-iododeoxyuridine: a new reagent for detection of DNA replication.
        Science. 1982; 218: 474-475
        • Aoyagi M
        • Yamamoto M
        • Wakimoto H
        • Azuma H
        • Hirakawa K
        • Yamamoto K
        Immunohistochemical detection of Ki-67 in replicative smooth muscle cells of rabbit carotid arteries after balloon denudation.
        Stroke. 1995; 26: 2328-2332
        • Zeymer U
        • Fishbein MC
        • Forrester JS
        • Cercek B
        Proliferating cell nuclear antigen: Immunohistochemistry in rat aorta after balloon denudation.
        Am J Pathol. 1992; 141: 685-690
        • Cybulsky MI
        • Gimbrone MAJ
        Endothelial expression of a mononuclear leukocyte adhesion molecule during atherogenesis.
        Science. 1991; 251: 788-791
        • Baumgartner HR
        • Studer A
        Folgen des gefässkatheterismus am normo- und hypercholesterinaemischen kaninchen.
        Path Microbiol. 1966; 29: 393-405
        • Weidinger FF
        • McLenachan JM
        • Cybulsky MI
        • Fallon JT
        • Hollenberg NK
        • Cooke JP
        • Ganz P
        Hypercholesterolemia enhances macrophage recruitment and dysfunction of regenerated endothelium after balloon injury of the rabbit iliac artery.
        Circulation. 1991; 84: 755-767
        • Andersen HO
        • Holm P
        • Nordestgaard BG
        • Hansen BF
        • Kjeldsen K
        • Elinder LS
        • Stender S
        Effect of the antioxidant probucol on transplant arteriosclerosis in aorta-allografted rabbits.
        J Mol Cell Cardiol. 1995; 27: 1561-1571
        • Wilensky RL
        • March KL
        • Gradus Pizlo I
        • Sandusky G
        • Fineberg N
        • Hathaway DR
        Vascular injury, repair, and restenosis after percutaneous transluminal angioplasty in the atherosclerotic rabbit.
        Circulation. 1995; 92: 2995-3005
        • Bondjers G
        • Björkerud S
        Arterial repair and atherosclerosis after mechanical injury. Part 4. Uptake and composition of cholesteryl ester in morphologically defined regions of atherosclerotic lesions.
        Atherosclerosis. 1972; 15: 273-284
        • Reidy MA
        • Schwartz SM
        Endothelial regeneration. (III). Time course of intimal changes after small defined injury to rat aortic endothelium.
        Lab Invest. 1981; 44: 301-308
        • Betz E
        • Schlote W
        Responses of vessel walls to chronical applied electrical stimuli.
        Basic Res Cardiol. 1979; 74: 10-20
        • Kling D
        • Holzschuh T
        • Strohschneider T
        • Betz E
        Enhanced endothelial permeability and invasion of leukocytes into the artery wall as initial events in experimental arteriosclerosis.
        Int Angiol. 1987; 6: 21-28
        • Betz E
        • Hämmerle H
        Arterienwandproliferate und zellkulturen als indikatoren für hemmstoffe der atherogenese.
        Funkt Biol Med. 1984; 3: 46-55
        • Hanke H
        • Strohschneider T
        • Oberhoff M
        • Betz E
        • Karsch KR
        Time course of smooth muscle cell proliferation in the intima and media of arteries following experimental angioplasty.
        Circ Res. 1990; 67: 651-659
        • Soma MR
        • Donetti E
        • Parolini C
        • Mazzini G
        • Ferrari C
        • Fumagalli R
        • Paoletti R
        HMG CoA reductase inhibitors. In vivo effects on carotid intimal thickening in normocholesterolemic rabbits.
        Arterioscler Thromb. 1993; 13: 571-578
        • Israel O
        Experimentelle untersuchung über den zusammenhang zwischen nierenkrankheiten und secundären veränderungen des circulationssystems.
        Virchow Arch Pathol Anat. 1881; 86: 299-321
        • Campbell DJ
        • Day AJ
        • Skinner SL
        • Tume RK
        The effect of hypertension on the accumulation of lipids and the uptake of (3H)cholesterol by the aorta of normal-fed and cholesterol-fed rabbits.
        Atherosclerosis. 1973; 18: 301-319
        • Chobanian AV
        • Lichtenstein AH
        • Nilakhe V
        • Haudenschild CC
        • Drago R
        • Nickerson C
        Influence of hypertension on atherosclerosis in the Watanabe rabbit.
        Hypertension. 1989; 14: 203-209
        • Spence JD
        • Perkins DG
        • Kline RL
        • Adams MA
        • Haust MD
        Hemodynamic modification of aortic atherosclerosis. Effects of propranolol vs hydralazine in hypertensive hyperlipidemic rabbits.
        Atherosclerosis. 1984; 50: 325-333
        • Duff GL
        • McMillan GC
        The effect of alloxan diabetes on experimental cholesterol atherosclerosis in the rabbit. I. The inhibition of experimental cholesterol atherosclerosis in alloxan diabetes. II. The effect of alloxan diabetes on the retrogression of experimental cholesterol atherosclerosis.
        J Exp Med. 1949; 89: 611-630
        • Nordestgaard BG
        • Zilversmit DB
        Large lipoproteins are excluded from the arterial wall in diabetic cholesterol-fed rabbits.
        J Lipid Res. 1988; 29: 1491-1500
        • Nordestgaard BG
        • Zilversmit DB
        Hyperglycemia in normotriglyceridemic, hypercholesterolemic insulin-treated diabetic rabbits does not accelerate atherogenesis.
        Atherosclerosis. 1988; 72: 37-47
        • Voisard R
        • Jensch V
        • Baur R
        • Höher M
        • Hombach V
        A coronary porcine organ culture system for studies of postangioplasty cell proliferation.
        Coron Art Dis. 1995; 6: 657-665
        • Fingerle L
        • Kraft T
        The induction of smooth muscle cell proliferation in vitro using an organ culture system.
        Int Angiol. 1987; 6: 65-72
      3. Wolburg-Buchholz K, Fallier-Becker P, Roth DR, Betz EL. Transfilter coculture system with vessel wall cells under the influence of monocytes and LDL: a model for in vitro plaque formation. In: Zilla P, Fasol R, Callow A, editors. Applied Cardiovascular Biology 1990–91. 1st ed. Karger: Basel, 1992:65–69.

        • Ludden JB
        • Bruger M
        • Wright IS
        Effect of testosterone propionate and estradiol dipropionate on experimental atherosclerosis in rabbits.
        Arch Pathol. 1942; 33: 58-62
        • Riedel M
        • Rafflenbeul W
        • Lichtlen P
        Ovarian sex steroids and atherosclerosis.
        Clin Invest. 1993; 71: 406-412
        • Hayashi T
        • Fukuto JM
        • Ignarro LJ
        • Chaudhuri G
        Basal release of nitric oxide from aortic rings is greater in female rabbits than in male rabbits: Implications for atherosclerosis.
        Proc Natl Acad Sci USA. 1992; 89: 11259-11263
        • Gerhard M
        • Ganz P
        How do we explain the clinical benefits of estrogen? From bedside to bench.
        Circulation. 1995; 92: 5-8
        • Karas RH
        • Patterson BL
        • Mendelsohn ME
        Human vascular smooth muscle cells contain functional estrogen receptor.
        Circulation. 1994; 89: 1943-1950
        • Venkov CD
        • Rankin AB
        • Vaughan DE
        Identification of authentic estrogen receptor in cultured endothelial cells. A potential mechanism for steroid hormone regulation of endothelial function.
        Circulation. 1996; 94: 727-733
        • Losordo DW
        • Kearney M
        • Kim EA
        • Jekanowski J
        • Isner JM
        Variable expression of the estrogen receptor in normal and atherosclerotic coronary arteries of premenopausal women.
        Circulation. 1994; 89: 1501-1510
        • Lin AL
        • Gonzalez R
        • Carey KD
        • Shain SA
        Estradiol-17-beta affects estrogen receptor distribution and elevates progesterone receptor content in baboon aorta.
        Arteriosclerosis. 1986; 6: 495-504
        • Hanke H
        • Hanke S
        • Finking G
        • Muhic Lohrer A
        • Muck AO
        • Schmahl FW
        • Haasis R
        • Hombach V
        Different effects of estrogen and progesterone on experimental atherosclerosis in female versus male rabbits. Quantification of cellular proliferation by bromodeoxyuridine.
        Circulation. 1996; 94: 175-181
        • Anthony MS
        • Clarkson TB
        • Hughes Jr, CL
        • Morgan TM
        • Burke GL
        Soybean isoflavones improve cardiovascular risk factors without affecting the reproductive system of peripubertal rhesus monkeys.
        J Nutr. 1996; 126: 43-50
      4. Saltykow S. Atherosklerose bei Kaninchen nach wiederholter Staphylokokkeninjektion. In: Aschoff L, Marchand F, editors. Beitrage Pathology Anatomy. 43rd ed. Jena: Fischer, 1908:147–176.

        • Klurfeld DM
        • Allison MJ
        • Gerszten E
        • Dalton HP
        Alterations of host defenses paralleling cholesterol-induced atherogenesis. I. Interactions of prolonged experimental hypercholesterolemia and infections.
        J Med. 1979; 10: 35-48
        • Melnick JL
        • Adam E
        • Debakey ME
        Cytomegalovirus and atherosclerosis.
        Eur Heart J. 1993; 14: 30-38
        • Visser MR
        • Vercellotti GM
        Herpes simplex virus and atherosclerosis.
        Eur Heart J. 1993; 14: 39-42
        • Mattila KJ
        Viral and bacterial infections in patients with acute myocardial infarction.
        J Int Med. 1989; 225: 293-296
        • Benditt EP
        • Benditt JM
        Evidence for a monoclonal origin of human atherosclerotic plaques.
        Proc Nat Acad Sci USA. 1973; 70: 1753-1756
        • Nieminen NS
        • Mattila K
        • Valtonen V
        Infection and inflammation as risk factors for myocardial infarction.
        Eur Heart J. 1993; 14: 12-16
        • Saikku P
        • Leinonen M
        • Tenkanen L
        • Linnanmäki E
        • Ekman M-R
        • Manninen V
        • Mänttäri M
        • Frick H
        • Huttunen JK
        Chronic chlamydia pneumoniae infection as a risk factor for coronary heart disease in the Helsinki Heart Study.
        Ann Int Med. 1992; 116: 273-278
        • Kuo C-c
        • Gown AM
        • Benditt EP
        • Grayston JT
        Detection of Chlamydia pneumoniae in aortic lesions of atherosclerosis by immunocytological stain.
        Arterioscler Thromb. 1993; 13: 1501-1504
        • Moazed TC
        • Kuo C-c
        • Patton DL
        • Grayston JT
        • Campbell LA
        Experimental rabbit models of Chlamydia pneumoniae infection.
        Am J Pathol. 1996; 148: 667-676