The Development and Use of Animal Models in Atherosclerosis Research

  • Robert W. Wissler
  • Dragoslava Vesselinovitch
Part of the GWUMC Department of Biochemistry Annual Spring Symposia book series (GWUN)


There have been immense strides in the development and use of animal models of human atherosclerosis in the past 35 years. These are contributing greatly to the study of the cellular pathobiology and the molecular pathology and molecular genetics of this important disease process, studies that are difficult if not impossible in people. The purpose of this chapter is to trace these developments briefly and to highlight some of the ongoing studies that are likely to be especially useful and valuable in the near future.

Although the rabbit and fowl have been and still are making great contributions to our understanding of atherogenesis, the introduction of useful and highly relevant models of atherogenesis in large mammals has been particularly noteworthy, especially those developed in several species of nonhuman primates, swine, and the further development of canine models. These have helped make possible the study of the pathogenesis of progressive plaques leading to advanced lesions with most if not all of the cardiovascular, peripheral, and cerebral complications observed in human subjects. These studies have also permitted pioneering investigations of the cellular and biochemical events in progression as well as those resulting from therapeutic retardation of atherosclerosis using modern pathobiological and molecular methods. They form a fitting bridge between the exciting probes being made in vitro and the developing studies of human atherosclerotic lesions being conducted using surgically removed lesions and suitable specimens from freshly autopsied cadavers. They also form a bridge to the many epidemiologic studies, the results of which are sometimes difficult to confirm at the lesion level in human subjects.

Among the very recent useful developments that excite the imagination are the genetic models of lipoprotein abnormalities being developed in rabbits and in the baboon, the remarkable insights concerning the mechanisms responsible for hyper-and hyporesponders in several species of primates, the important studies of the influence of sex and other endocrine effects, of stress on behavior and sociological interactions in primates, the pioneering investigations of the effects of immune complexes and other arterial injuries on the disease process, and the use of these models to delineate further the mechanisms by which exercise, calcium channel blockers, ß blockers, and other important interventions can alter the atherosclerotic process.


Rhesus Monkey Nonhuman Primate Sodium Cholate Advanced Lesion Aortic Atherosclerosis 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Anitschkow, N., 1913, Über die Veränderungen der Kaninchenaorta bei experimenteller Cholesterin-steatose, Beitr. Pathol. Anat. 56:379–404.Google Scholar
  2. Anitschkow, N., 1928, Über die Rückbildungsvorgänge bei der experimentellen Atherosklerose, Verh. Deut. Pathol. Gesellsch. 23:473–478.Google Scholar
  3. Benditt, E. P., Barrett, T., and McDougal, J. K., 1983, Viruses in the etiology of atherosclerosis, Proc. Natl. Acad. Sci. U.S.A. 80:6386–6389.PubMedCrossRefGoogle Scholar
  4. Bevans, M., Davidson, J. D., and Kendal, F. E., 1951, Regression of lesions in canine arteriosclerosis, Arch. Pathol. 51:288–292.Google Scholar
  5. Bowie, E. J. W., and Fuster, V., 1980, Resistance to atherosclerosis in pigs with von Willebrand’s disease, Acta Med. Scand [Suppl.] 642:121–130.Google Scholar
  6. Bragdon, J. H., Zeller, J. H., and Stevenson, J. W., 1957, Swine and experimental atherosclerosis, Proc. Soc. Exp. Biol. Med. 95:282–284.PubMedGoogle Scholar
  7. Buja, L. M., Kita, T., Goldstein, J. L., Watanabe, Y., and Brown, M. S., 1983, Cellular pathology of progressive atherosclerosis in the WHHL rabbit. An animal model of familial hypercholesterolemia, Arteriosclerosis 3:87–101.PubMedCrossRefGoogle Scholar
  8. Bullock, B. C., Lehner, N. D. M., Clarkson, T. B., Feldner, M. A., Wagner, W. D., and Lofland, H. B., 1975, Comparative primate atherosclerosis. I. Tissue cholesterol concentrations and pathologic anatomy, Exp. Mol. Pathol. 22:151–175.PubMedCrossRefGoogle Scholar
  9. Clarkson, T. B., 1974, Arteriosclerosis of African green and stump-tailed macaque monkeys, in Ath erosclerosis III (G. Schettler and A. Weizel, eds.), Springer-Verlag, New York, pp. 291–294.Google Scholar
  10. Clarkson, T. B., and Lofland, H. B., 1961, Effects of cholesterol-fat diets on pigeons susceptible and resistant to atherosclerosis, Circ. Res. 9:106–109.PubMedGoogle Scholar
  11. Clarkson, T. B., Prichard, R. W., Netsky, M. G., and Lofland, H. B., 1959, Atherosclerosis in pigeons. Its spontaneous occurrence and resemblance to human atherosclerosis, Arch. Pathol. 68:143–147.Google Scholar
  12. Clarkson, T. B., Prichard, R. W., Lofland, H. B., and Goodman, H. O., 1962, Interactions among dietary fat, protein, and cholesterol in atherosclerosis-susceptible pigeons, Circ. Res. 11:400–404.Google Scholar
  13. Clarkson, T. B., Lofland, H. B., Bullock, B. C., and Goodman, H. O., 1971, Genetic control of plasma cholesterol. Studies on squirrel monkeys, Arch. Pathol. 92:37–45.PubMedGoogle Scholar
  14. Clarkson, T. B., Lehner, N. D. M., Bullock, B. C., Lofland, H. B. and Wagner, W. D., 1976, Atherosclerosis in New World monkeys, Primates Med. 9:90–144.PubMedGoogle Scholar
  15. Daoud, A. S., Jarmolych, J., Augustyn, J. M., and Fritz, K. E., 1981, Sequential morphologic studies of regression of advanced atherosclerosis, Arch. Pathol. 105:233–239.Google Scholar
  16. Dauber, D. V., and Katz, L. N., 1943, Experimental atherosclerosis in the chick, Arch. Pathol. 36:473–492.Google Scholar
  17. Fabricant, C. G., Fabricant, J., Minick, C. R., and Litrenta, M. M., 1983, Herpesvirus-induced atherosclerosis in chickens, Fed. Proc. 42:2476–2479.PubMedGoogle Scholar
  18. Faggiotto, A., and Ross, R., 1984, Studies of hypercholesterolemia in the nonhuman primate: II. Fatty streak conversion to fibrous plaque, Arteriosclerosis 4:341–356.PubMedCrossRefGoogle Scholar
  19. Faggiotto, A., Ross, R., and Harker, L., 1984, Studies of hypercholesterolemia in the nonhuman primate: I. Changes that lead to fatty streak formation, Arteriosclerosis 4:323–340.PubMedCrossRefGoogle Scholar
  20. Fantone, J. C. and Ward, P. A., 1982, Role of oxygen-derived free radicals and metabolites in leukocyte-dependent inflammatory reactions, Am. J. Pathol. 107:395–416.PubMedGoogle Scholar
  21. Fillios, L. C., Andrus, S. B., Mann, G. V., and Stare, F. J., 1956, Experimental production of gross atherosclerosis in the rat, J. Exp. Med. 104:539–554.PubMedCrossRefGoogle Scholar
  22. Fritz, K. E., Augustyn, J. M., Jarmolych, J., and Daoud, A. S., 1981, Sequential study of biochemical changes during regression of swine aortic atherosclerotic lesions, Arch. Pathol. 105:240–246.Google Scholar
  23. Griggs, T. R.,Reddick, R. L., Seltzer, D., and Brinkhous, K. M., 1981, Susceptibility to atherosclerosis in aortas and coronary arteries of swine with von Willebran disease, Am. J. Pathol. 102:137–145.PubMedGoogle Scholar
  24. Howard, C. F., Jr., 1979, Aortic atherosclerosis in normal spontaneously diabetic Macaca nigra, Atherosclerosis 33:479–493.PubMedCrossRefGoogle Scholar
  25. Howard, C. F., Jr., Vesselinovitch, D., and Wissler, R. W., 1984, Correlation of aortic histology with gross aortic atherosclerosis and metabolic measurements in diabetic and nondiabetic Macaca nigra, Atherosclerosis 52:85–100.PubMedCrossRefGoogle Scholar
  26. Ignatowski, A., 1908, I. Influence of animal food on the organism of rabbits, S.-Peterb. Izviest. Imp. Voyenno-Med Akad. 16:154–176.Google Scholar
  27. Innerarity, T. L., Pitas, R. E., and Mahley, R. W., 1982, Modulating effects of canine high density lipoproteins on cholesteryl ester synthesis induced by ß-very low density lipoproteins in macro phages: Possible in vitro correlates with atherosclerosis, Arteriosclerosis 2:114–124.PubMedCrossRefGoogle Scholar
  28. Jokinen, M. P., Clarkson, T. B., and Prichard, R. W., 1985, Animal models in atherosclerosis research, Exp. Mol. Pathol.42:1–28.PubMedCrossRefGoogle Scholar
  29. Kramsch, D. M., and Hollander, W., 1968, Occlusive atherosclerotic disease of the coronary arteries in monkeys (Macaca irus) induced by diet, Exp. Mol. Pathol. 9:1–22.PubMedCrossRefGoogle Scholar
  30. Lofland, H. B., and Clarkson, T. B., 1960, Serum lipoproteins in atherosclerosis-susceptible and resistant pigeons, Proc. Soc. Exp. Biol. Med. 103:238–241.PubMedGoogle Scholar
  31. Mahley, R. W., Weisgraber, K. H., and Innerarity, T., 1974, Canine lipoproteins and atherosclerosis: II. Characterization of the plasma lipoproteins associated with atherogenic and nonatherogenic hyperlipidemia, Circ. Res. 35:722–733.PubMedGoogle Scholar
  32. Mahley, R. W., Weisgraber, K. H., Innerarity, T., and Brewer, H. B., 1976, Characterization of the plasma lipoproteins and apoproteins of the Erythrocebus patas monkey, Biochemistry 15:1928–1933.PubMedCrossRefGoogle Scholar
  33. Mahley, R. W., Johnson, D. K., Pucak, G. J., and Fry, D. L., 1980, Atherosclerosis in the Erythrocebus patas ,an Old World monkey, Am. J. Pathol. 98:401–424.PubMedGoogle Scholar
  34. Malinow, M. R., and Blaton, V. H. (eds.), 1984, Regression of Atherosclerotic Lesions ,Plenum Press, New York.Google Scholar
  35. Malmros, H., and Wigand, G., 1965, Experimental hypercholesterolemia and hypertriglyceridemia in cynomolgus monkeys fed saturated fat and cholesterol, J. Athero. Res. 5:474–482.CrossRefGoogle Scholar
  36. Maruffo, C. A., and Portman, O. W., 1968, Nutritional control of coronary artery atherosclerosis in the squirrel monkey, J. Athero. Res. 8:237–247.CrossRefGoogle Scholar
  37. McGill, H. C., Jr., Strong, J. P., Holman, R. L., and Werthessen, N. T., 1960, Arterial lesions in the Kenya baboon, Circ. Res. 8:670–679.Google Scholar
  38. McGill, H. C., Jr., Frank, M. H., and Geer, J. C., 1961, Aortic lesions in the hypertensive monkeys, Arch. Pathol. 71:96–102.Google Scholar
  39. Melnick, J. L., Petrie, B. L., Dreesman, G. R., Burek, J., Mc-Collum, C. H., and DeBakey, M. E., 1983, Cytomegalovirus antigen within human arterial smooth muscle cells, Lancet 2:644–647.PubMedCrossRefGoogle Scholar
  40. Middleton, C. C., Clarkson, T. B., Lofland, H. B., and Prichard, R. W., 1964, Atherosclerosis in the squirrel monkey. Naturally occurring lesions of the aorta and coronary arteries, Arch. Pathol. 78:16–23.PubMedGoogle Scholar
  41. Minick, C. R., and Murphy, G. E., 1973, Experimental induction of athero-arteriosclerosis by the synergy of allergic injury to arteries and lipid rich diet: II. Effect of repeatedly injected foreign protein in rabbits fed a lipid rich cholesterol poor diet, Am. J. Pathol. 73:265–292.PubMedGoogle Scholar
  42. Minick, C. R., Fabricant, C. G., Fabricant, J., and Litrenta, M. M., 1979, Atheroarteriosclerosis induced by infection with a herpes virus, Am. J. Pathol. 96:673–706.PubMedGoogle Scholar
  43. Peng, S. K., Taylor, C. B., Tham, P., Werthessen, N. T., and Mikkelson, B., 1978, Effect of auto-oxidation products from cholesterol on aortic smooth muscle cells: An in vitro study, Arch. Pathol. 102:57–61.Google Scholar
  44. Prichard, R. W., Clarkson, T. B., Lofland, H. B., Goodman, H. O., Herndon, C. N., and Netsky, M. G., 1962, Studies on the atherosclerotic pigeon, J.A.M.A. 179:49–52PubMedCrossRefGoogle Scholar
  45. Prichard, R. W., Clarkson, T. B., and Goodman, H. O., 1964, Aortic atherosclerosis in pigeons and its complications, Arch. Pathol. 77:244–257.PubMedGoogle Scholar
  46. Reidy, M. A., and Schwartz, S. M., 1983, Endothelial injury and regeneration. IV. Endotoxin: A non-denuding injury to aortic endothelium, Lab. Invest. 48:25–34.PubMedGoogle Scholar
  47. Reidy, M. A., Clowes, A. W., and Schwartz, S. M., 1983, Endothelial Regeneration V. Inhibition of endothelial regrowth in arteries of rat and rabbit, Lab. Invest. 49:569–575.PubMedGoogle Scholar
  48. Robertson, A. L., Jr., Butkus, A., Ehrhart, L. A., and Lewis, L. A., 1972, Experimental arteriosclerosis in dogs. Evaluation of anatomopathological findings, Atherosclerosis 15:307–325.PubMedCrossRefGoogle Scholar
  49. Rudel, L. L., and Bullock, B.C., 1981, Low density lipoprotein-atherosclerosis relationships in African green monkeys, Fed. Proc. 40:345.Google Scholar
  50. Steiner, A., and Kendall, F. E., 1946, Atherosclerosis and arteriosclerosis in dogs following ingestion of cholesterol and thiouracil, Arch. Pathol. 42:433–444.Google Scholar
  51. Steiner, A., Kendall, F. E., and Bevans, M., 1949, Production of arteriosclerosis in dogs by cholesterol and thiouracil feeding, Am. Heart J. 38:34–42.PubMedCrossRefGoogle Scholar
  52. Stemerman, M. B., and Ross, R., 1972, Experimental arteriosclerosis. I. Fibrous plaque formation in primates, an electron microscope study, J. Exp. Med. 136:769–789.PubMedCrossRefGoogle Scholar
  53. Stills, H. F., Jr., and Bullock, B. C., 1981, Renal disease in squirrel monkeys (Saimiri sciureus), Vet. Pathol. 18(Suppl. 6):38–44.PubMedGoogle Scholar
  54. Taylor, C. B., Cox, G. E., Counts, M., and Yogi, N., 1959, Fatal myocardial infarction in the rhesus monkey with diet-induced hypercholesterolemia, Am. J. Pathol. 35:674.Google Scholar
  55. Taylor, C. B., Cox, G. E., Manalo-Estrella, P., Southworth, J., Patton, D. E., and Cathcart, C., 1962, Atherosclerosis in rhesus monkeys: II. Arterial lesions associated with hypercholesteremia induced by dietary fat and cholesterol, Arch. Pathol. 74:16–34.PubMedGoogle Scholar
  56. Taylor, C. B., Manalo-Estrella, P., and Cox, G. E., 1963a, Atherosclerosis in rhesus monkeys: V. Marked diet-induced hypercholesteremia with xanthomatosis and severe atherosclerosis, Arch. Pathol. 76:239–249.PubMedGoogle Scholar
  57. Taylor, C. B., Patton, D. E., and Cox, G. E., 1963b, Atherosclerosis in rhesus monkeys: VI. Fatal myocardial infarction in a monkey fed fat and cholesterol, Arch. Pathol. 76:404–412.PubMedGoogle Scholar
  58. Taylor, C. B., Peng, S. K., Werthessen, N. T., Tham, P., and Lee, K. T., 1979, Spontaneously occurring angiotoxic derivatives of cholesterol, Am. J. Clin. Nutr. 32:40–57.PubMedGoogle Scholar
  59. Thomas, W. A., and Hartroft, W. S., 1959, Myocardial infarction in rats fed diets containing high fat, cholesterol, thiouracil and sodium cholate, Circulation 19:65–72.PubMedGoogle Scholar
  60. Thomas, W. A., Kim, D. N., Lee, K. T., Reiner, J. M., and Schmee, J., 1983, Population dynamics of arterial cells during atherogenesis. XIII. Mitogenic and cytotoxic effects of a hyperlipidemic (HL) diet on cells in advanced lesions in the abdominal aortas of swine fed an HL diet for 270–345 days, Exp. Mol. Pathol. 39:257–270.PubMedCrossRefGoogle Scholar
  61. Vesselinovitch, D., and Wissler, R. W., 1968, Experimental production of atherosclerosis in mice. II. Effects of atherogenic and high-fat diets on vascular changes in chronically and acutely irradiated mice, J. Athero. Res. 8:497–523.CrossRefGoogle Scholar
  62. Vesselinovitch, D., and Wissler, R. W., 1983, Quantitation of certain qualitative differences in the atherosclerotic process, in: Atherosclerosis VI (G. Schettler, A. M. Gotto, G. Middelhoff, A. S. Habenicht, and K. R. Jurutka, eds.), Springer-Verlag, Berlin, pp. 174–179.CrossRefGoogle Scholar
  63. Vesselinovitch, D., Getz, G. S., Hughes, R. H., and Wissler, R. W., 1974, Atherosclerosis in the rhesus monkey fed three food fats, Atherosclerosis 20:303–321.PubMedCrossRefGoogle Scholar
  64. Vesselinovitch, D., Wissler, R. W., Schaffner, T. J., and Borensztojn, J., 1980, The effects of various diets on atherogenesis in rhesus monkeys, Atherosclerosis 35:198–207.CrossRefGoogle Scholar
  65. Wagner, W. D., and Clarkson, T. B., 1975, Comparative primate atherosclerosis. II. A biochemical study of lipids, calcium, and collagen in atherosclerotic arteries, Exp. Mol. Pathol. 23:96–121.PubMedCrossRefGoogle Scholar
  66. Wissler, R. W., 1984, The pathobiology of the atherosclerotic plaque in the mid-1980s, in: Regression of Atherosclerotic Lesions (M. R. Malinow and V. H. Blaton, eds.), Plenum Press, New York, pp. 5–20.Google Scholar
  67. Wissler, R. W., 1985, Atherosclerosis: A preventable and potentially reversible disease process, in: Frontiers in Medicine. Implications for the Future (R. J. Morin and R. J. Bing, eds.), Human Sciences Press, New York, pp. 19–46.Google Scholar
  68. Wissler, R. W., and Vesselinovitch, D., 1968, Experimental models of human atherosclerosis, Ann. N.Y. Acad. Sci. 149:907–922.PubMedGoogle Scholar
  69. Wissler, R. W., and Vesselinovitch, D., 1977, Atherosclerosis in non-human primates, in: Advances in Veterinary Science and Comparative Medicine (C. A. Brandly, C. E. Cornelius, and C. F. Simpson, eds.), Academic Press, New York, pp. 351–420.Google Scholar
  70. Wissler, R. W., and Vesselinovitch, D., 1978, Evaluation of animal models for the study of the pathogenesis of atherosclerosis, in: International Symposium State of Prevention and Therapy in Human Arteriosclerosis and in Animal Models (W. H. Hauss, R. W. Wissler, and R. Lehmann, eds.), Westdeutscher-Verlag, Opladen, pp. 13–29.Google Scholar
  71. Wissler, R. W., and Vesselinovitch, D., 1983, Atherosclerosis-Relationship to coronary blood flow, Am. J. Cardiol. 52:2A–7A.PubMedCrossRefGoogle Scholar
  72. Wissler, R. W., and Vesselinovitch, D., 1984a, Interaction of therapeutic diets and cholesterol-lowering drugs in regression studies in animals, in: Regression of Atherosclerotic Lesions (M. R. Malinow and V. H. Blaton, eds.), Plenum Press, New York, pp. 21–41.Google Scholar
  73. Wissler, R. W., and Vesselinovitch, D., 1984b, New concepts of factors involved in the natural history and regression of atherosclerosis, Period. Angiol. 5:178–187.Google Scholar
  74. Wissler, R. W., Eilert, M. L., Schroeder, M. A., and Cohen, L., 1954, Production of lipomatous and atheromatous arterial lesions in the albino rat, Arch. Pathol. 57:333–351.Google Scholar
  75. Wissler, R. W., Vesselinovitch, D., Davis, H. R., Lambert, P. H., and Bekermeier, M., 1985, A new way to look at atherosclerotic involvement of the artery wall and the functional effects, Ann. N.Y. Acad. Sci. 454:9–22.PubMedCrossRefGoogle Scholar
  76. Yamashiroya, H. M., Ghosh, L., Yang, R., Parveen, T., and Robertson, A. L., Jr., 1986, Herpesviridae in coronary vessels and aorta of young asymptomatic trauma victims, Fed. Proc. 45:813.Google Scholar

Copyright information

© Plenum Press, New York 1987

Authors and Affiliations

  • Robert W. Wissler
    • 1
  • Dragoslava Vesselinovitch
    • 1
  1. 1.Department of PathologyUniversity of Chicago, Atherosclerosis-SCORChicagoUSA

Personalised recommendations