Thursday, October 13, 2011

Rabbit as an Animal Model for Atherosclerosis

Atherosclerosis naturally occurs only in humans, a few non-human primates, and pigs. Rabbits, being herbivores, do not develop atherosclerosis naturally, but do consistently develop an atherosclerotic condition that very closely resembles clinical observations when manipulated via dietary or genetic interventions. The rabbit hypercholesterolemia model is perhaps the most well-know of the models and is typically produced by feeding intact rabbits a high-cholesterol diet. After only a few weeks on a modified diet, rabbits develop notable vascular lesions. This rabbit model is highly reproducible with minimal variation between animals in a single laboratory and between laboratories. Two spontaneous lipid metabolism mutants have been characterized and also used extensively in atherosclerosis research – the Watanabe heritable hyperlipidemic (WHHL) rabbit (LDL receptor deficient) and the St. Thomas’ Hospital rabbit (VLDL, IDL, and LDL elevated) serve as models for familial hypercholesterolemia and familial combined hyperlipidemia, respectively. Homozygous WHHL rabbits and St. Thomas’ Hospital rabbits predictably develop atherosclerotic lesions on normal diets. Finally, there are at least 19 transgenic rabbit lines now available specifically for the study of cardiovascular disease that express a wide variety of human transgenes many of which code for proteins implicated in atherosclerosis. [1-3]

These rabbit models closely approximate a variety of aspects of human atherosclerosis and are commonly used to study atherogenesis, plaque instability and rupture, and myocardial infarction. Relative to rodent models, rabbits are much more clinically relevant as many aspects of rabbit lipoprotein metabolism are very similar to humans. Perhaps the most notable differences are that rabbit vascular lesions are more fatty and more inflammatory (as measured by numbers of macrophages present) and rabbit circulating cholesterol levels are higher. An additional advantage to rabbits over rodents is that human transgenes expressed in rabbits produce the expected human-like symptoms while the same transgenes expressed in rodents fail to do so. Further, rabbits are capable of tolerating longer experimental protocols that require monitoring and/or sampling over a period of time whereas individual rodents often can only contribute to a single time point in a study. [1-3]

Rabbit is the first and classical model for human atherosclerosis research and will continue contribute pre-clinical, translational evidence for the safety and efficacy of novel therapies. Perhaps the only animal models that have in some cases surpassed the value delivered by rabbits are the swine models. [1-3]

1. Bosze, Z. and Houdebine, L.M. (2006) Application of rabbits in biomedical research: a review. World Rabbit Sci. 14:1-14.

2. Badimon, L. et al. (2008) Models of behavior: cardiovascular. In: Conn, P.M. (ed.) Sourcebook of models for biomedical research. Humana Press, pp. 361-368.

3. Kónya, A. et al. (2008) Animal models for atherosclerosis, restenosis, and endovascular aneurysm repair. In: Conn, P.M. (ed.) Sourcebook of models for biomedical research. Humana Press, pp. 369-384.

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