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Editorial Slides VP Watch, January 16, 2002, Volume 2, Issue 2
Part II - Animal Models of Heart Attack? Plaque Rupture/Thrombosis
Part - I Cell culture is a convenient way to ask
mechanistic questions, but it lacks complexity of a real disease thus limiting the scope of testable hypotheses. Human observations provide rich soil for making hypotheses, but for obvious ethical reasons our ability to test these hypotheses in men is very limited. Animal models are essential for testing mechanistic hypotheses in a controlled manner.1
Ideal animal model is situated in the middle of this range. 1
1- Japanese quail
2- Pigeon
3- Chicken
Reported Animal Models for Atherosclerosis
4- Dog5- Monkey6- Pig7- Rat8- Rabbit9- Mouse
Quail:
- Studies on Japanese quail have shown that the RES birds were resistant to the disease and developed little atherosclerosis on a diet containing 1% cholesterol. The SUS birds were sensitive and developed severe atherosclerosis in 8-9 wks on a diet containing only 0.5% cholesterol. 14,15,16
Pigeon:
- Tesar and Kottke showed that two distinct types of fatty streaks can be identified in white Carneau pigeon and their biologic features can be defined and related to their propensity for atherogenesis.6
Chicken:
- Wong discussed that chicken is a good animal model for the study of atherosclerosis research because it is able to develop spontaneous atherosclerosis and capable of producing atherosclerosis after cholesterol feeding with elevated hypercholesterolemia. There is no essential difference between vascular lesions seen in chickens as a result of cholesterol diet and that of atherosclerosis observed in man.2,3
Dog:
- Reducing platelet accumulation at sites of balloon angioplasty may attenuate restenosis. Willerson, et al. tested this hypothesis by inducing repetitive platelet aggregation at coronary angioplasty sites in cholesterol sensitive dogs and measured subsequent neointima formation. 4,5
Monkey:
- Blaton and Peeters discussed that the chimpanzee lipoproteins are useful models for understanding the relationship between function and structure of the plasma lipoproteins in health and disease. Baboon and rhesus monkeys show similar results, but more differences to the human lipoproteins in health and disease were observed.8,9
Swine:
- Massmann, and others showed relations between spontaneous and induced arterial lesions in swine and arteriosclerosis in humans. 7,21
Rat:
- Bennani-Kabchi et al. showed the potential of the sand rat to develop atherosclerotic lesions at different stages which opens the field to therapeutic tests of new anti-atherogenic agents.
- More recently Herrera et al. demonstrated that cholesteryl ester transfer protein can be proatherogenic. The interaction of polygenic hypertension and hyperlipidemia in the pathogenesis of atherosclerosis in Tg [hCETP] DS rats substantiates epidemiological observations in humans.10,11
Rabbit:
- Hereditary Watanabe rabbit - Clubb et al. evaluated temporal distribution of leukocytes, macrophages, foam cells, vascular smooth muscle cells, and subendothelial lipid in Watanabe heritable hyperlipedimic (WHHL) rabbit aortas.19
- Cholesterol fed New Zealand rabbit - Atherosclerotic plaques were produced in New Zealand White rabbits by intermittent cholesterol feeding.20
Rekhter, et al. have developed a rabbit model in which an atherosclerotic plaque can be ruptured at will after an inflatable balloon becomes embedded into the plaque. This model as well can be used for induction of thrombi associated with plaque rupture. 17
Mouse:
- The apoE-deficient mouse contains the entire spectrum of lesions observed during atherogenesis and is the first mouse model to develop lesions similar to those in humans. 12,13
Part - II The process of atherosclerotic plaque disruption has
been difficult to monitor because of the lack of an animal model of plaque rupture. 23
More than 30 years ago, Constantinides and Chakravarti triggered plaque rupture and thrombosis in aorta of chlolesterol fed rabbits by intraperitoneal injection of Russell's viper venom (RVV, a potent procoagulant and endothelial toxin) followed by the intravenous injection of histamine, a vasopressor. 25
The aortas of the rabbits were then accordingly found to have disrupted atherosclerotic plaques with overlying platelet-rich thrombi. 25
The advantage of Constantinides model is use of a biological intervention for triggering localized plaque thrombosis. However the non-physiological use of a toxic and potent thrombogenic substance (snake toxin) to induce plaque thrombosis can be considered a major drawback. 24
Other disadvantages of the Constantinides model are the low yield of triggering (only about one third of the rabbits developed thrombosis) and the long (8-month) preparatory period. 24
Abela, Muller and colleagues challenged the limitations of Constantinides model by having the rabbits undergo aortic balloon injury followed by 8 weeks of 1% cholesterol diet. 24
In addition, they wanted to determine whether mechanical injury to the aorta early in the preparatory phase could enhance the development of vulnerable plaques, thereby increasing the yield of disrupted plaques and shortening the preparatory period. the rate of plaque disruption after pharmacological triggering increased to 71%. 24
They found that the rate of plaque disruption after pharmacological triggering increased up to 71%.24
Johnstone, Manning, and colleagues used the modified Constantinides model and documented plaque disruption by MRI that resemble those found in human coronary arteries. 23
A major advantage of the use of a rabbit over other animals is that the rabbit’s aorta is approximately the same anatomic size as the human coronary artery. 23
As highlighted in this week of VP Watch, Braun, Krieger, et al. showed that mice with homozygous null mutations in the genes for both the LDL and apoE receptors (SR-BI/apoE double knockout mice) exhibit morphological and functional defects with similarities to those seen in human coronary heart disease.22
The SR-BI/apoE dKO mice are distinct because they have extensive coronary artery lesions with fibrin deposition and spontaneously develop extensive MIs on a standard chow diet at a very young age (5 weeks).22
The authors indicated that severe occlusive, fibrin-containing coronary arterial lesions, probable ischemia, multiple MIs, enlarged hearts, and cardiac dysfunction in very young ('5 weeks old), low-fat/ low-cholesterol fed SR-BI/apoE dKO mice provide a novel model of CHD.22
Fibrin deposits were found in the core regions of 8 of 10 lesions in 3 of 3 dKO mice.22
However, clear evidence for plaque rupture was not found in these animals neither was thin fibrous cap.22
Conclusion:I. Comparing to the previous animal models of
atherosclerosis, double knockout LDL/apoE mice seem to offer an improvement in studying the clinical complications of atherosclerosis closer to human ischemic heart disease.
II. However, it is unclear as to what degree the new model simulates the pathophysiology and pathology characteristic of human vulnerable atherosclerotic plaques.
Questions:1. Which one the following animal models more closely
resembles human coronary artery disease?
- Watanabe rabbits
- New Zealand cholesterol fed rabbits
- CETP/DS transgenic rat
- Apo-E deficient mice
- LDL deficient mice
- Double KO LDL/apoE mice
Questions:2. Since clinical atherosclerosis is predominantly an
athero-thrombotic disease, besides the plaque characteristics in these animals, the question is how closely their blood factors and coagulation system resembles of those in human?
3. Since transgenic animal models of atherosclerosis do not live long, knowing the major role of age in the natural history of human atherosclerosis and its complications such as plaque rupture, can we find a representative model of repeated plaque rupture in these animals.
Suggestion:VP.org Editorial Suggestion:
- Please email your thoughts to:
1. Rekhter MD, Hicks GW, Brammer DW, Work CW, Kim JS, Gordon D, Keiser JA, Ryan MJ.Animal model that mimics atherosclerotic plaque rupture. Circ Res. 1998 Oct 5;83(7):705-13.
2. Wong HY; The cockerel as an animal model for atherosclerosis research. Adv Exp Med Biol. 1975;63:381-91.
3. Lucas A, Yue W, Jiang XY, Liu L, Yan W, Bauer J, Schneider W, Tulip J, Chagpar A, Dai E, Perk M,Montague P, Garbutt M, Radosavljevic M. Development of an avian model for restenosis. Atherosclerosis. 1996 Jan 5;119(1):17-41.
4. Folts JD, Crowell EB, Rowe GG. Platelet aggregation in partially obstructed vessels and its elimination with aspirin. Circulation. 1976; 54: 365–370.
5. Anderson HV, McNatt J, Clubb FJ, Herman M, Maffrand JP, DeClerck F, Ahn C, Buja LM, Willerson JT.; Platelet inhibition reduces cyclic flow variations and neointimal proliferation in normal and hypercholesterolemic-atherosclerotic canine coronary arteries.; Circulation. 2001 Nov 6;104(19):2331-7.
6. Tesar GE, Kottke BA.; Location and sequence of atherosclerotic plaque formation in white Carneau and show racer pigeons: reevaluation and redefinition.Arch Pathol Lab Med. 1978 Nov;102(11):581
7. Massmann J, Muller H, Weidenbach H, Wagner J, Krug H.; Relations between spontaneous and induced arterial lesions in swine and arteriosclerosis in humans. Exp Pathol (Jena). 1977 Jul- Aug;14(1-2):89-99
8. Blaton V, Peeters H.; The nonhuman primates as models for studying human atherosclerosis: studies on the chimpanzee, the baboon and the rhesus macacus.Adv Exp Med Biol. 1976;67(00):33-64.
9. Daum G, Pham J, Deou J.; Arsenite inhibits Ras-dependent activation of ERK but activates ERK in the presence of oncogenic Ras in baboon vascular smooth muscle cells.; Mol Cell
Biochem. 2001 Jan;217(1-2):131-6.
References
10. Herrera VL, Makrides SC, Xie HX, Adari H, Krauss RM, Ryan US, Ruiz-Opazo N.; Spontaneous combined hyperlipidemia, coronary heart disease and decreased survival in Dahl salt-sensitive hypertensive rats transgenic for human cholesteryl ester transfer protein.; Nat Med. 1999 Dec;5(12):1383-9.
11. Bennani-Kabchi N, Kehel L, el Bouayadi F, Fdhil H, Amarti A, Saidi A, Marquie G.; New model of atherosclerosis in sand rats subjected to a high cholesterol diet and vitamin D2. Therapie. 1999 Sep-Oct;54(5):559-65.
12. Nakashima Y, Plump AS, Raines EW, Breslow JL, Ross R. ApoE-deficient mice develop lesions of all phases of atherosclerosis throughout the arterial tree. Arterioscler Thromb. 1994 Jan;14(1):133-40.
13. Saiura A, Sata M, Hirata Y, Nagai R, Makuuchi M.; Tranilast inhibits transplant-associated coronary arteriosclerosis in a murine model of cardiac transplantation. Eur J Pharmacol. 2001 Dec 21;433(2-3):163-8.
14. Velleman SG, McCormick RJ, Ely D, Jarrold BB, Patterson RA, Scott CB, Daneshvar H, Bacon WL. Collagen characteristics and organization during the progression of cholesterol-induced atherosclerosis in Japanese quail. Exp Biol Med (Maywood). 2001 Apr;226(4):328-33.
15. Wu TC, Donaldson WE. Effect of cholesterol feeding on serum lipoproteins and atherosclerosis in atherosclerosis-susceptible and atherosclerosis-resistant Japanese quail. Poult Sci. 1982 Dec;61(12):2407-14.
16. Shih JC, Pullman EP, Kao KJ.; Genetic selection, general characterization, and histology of atherosclerosis-susceptible and -resistant Japanese quail. Atherosclerosis. 1983 Oct;49(1):41-
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17. Rekhter MD, Hicks GW, Brammer DW, Work CW, Kim J-S, Gordon D, Keiser JA, Ryan MJ: Animal model that mimics atherosclerotic plaque rupture. Circ.Res. 1998;83:705-713
18. Plump AS, Smith JD, Hayek T, Aalto-Setala K, Walsh A, Verstuyft JG, Rubin EM, Breslow JL. Severe hypercholesterolemia and atherosclerosis in apolipoprotein E-deficient mice created by homologous recombination in ES cells. Cell. 1992 Oct 16;71(2):343-53.
19. Clubb FJ, Cerny JL, Deferrari DA, Butler-Aucoin MM, Willerson JT, Buja LM.Development of atherosclerotic plaque with endothelial disruption in Watanabe heritable hyperlipidemic rabbit aortas.Cardiovasc Pathol. 2001 Jan-Feb;10(1):.
20. Johnstone MT, Botnar RM, Perez AS, Stewart R, Quist WC, Hamilton JA, Manning WJ.In vivo magnetic resonance imaging of experimental thrombosis in a rabbit model.Arterioscler Thromb Vasc Biol. 2001 Sep;21(9):1556-60.
21. Wentzel JJ, Kloet J, Andhyiswara I, Oomen JA, Schuurbiers JC, de Smet BJ, Post MJ, de Kleijn D, Pasterkamp G, Borst C, Slager CJ, Krams R.Shear-stress and wall-stress regulation of vascular remodeling after balloon angioplasty: effect of matrix metalloproteinase inhibition.Circulation. 2001 Jul 3;104(1):91-6.
22. Anne Braun, Bernardo L. Trigatti, Mark J. Post, Kaori Sato, Michael Simons, Jay M. Edelberg, Robert D. Rosenberg, Mark Schrenzel, and Monty Krieger Loss of SR-BI Expression Leads to the Early Onset of Occlusive Atherosclerotic Coronary Artery Disease, Spontaneous Myocardial Infarctions, Severe Cardiac Dysfunction, and Premature Death in Apolipoprotein E--Deficient Mice Circulation Research published January 3, 2002, 10.1161/hh0302.104462
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Hamilton, and Warren J. Manning; In Vivo Magnetic Resonance Imaging of Experimental Thrombosis in
a Rabbit Model ; Arterioscler Thromb Vasc Biol 2001 21: 1556-1560.
24. George S. Abela, Paulo D. Picon, Stephan E. Friedl, Otavio C. Gebara, Akira Miyamoto, Micheline Federman, Geoffrey H. Tofler, and James E. Muller ; Triggering of Plaque Disruption and
Arterial Thrombosis in an Atherosclerotic Rabbit Model; Circulation 1995 91: 776-784.
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27. Skinner MP, Yuan C, Mitsumori L, Hayes CE, Raines EW, Nelson JA, Ross R. Serial magnetic
resonance imaging of experimental atherosclerosis detects lesion fine structure, progression and
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