© 2003 by European Society of Cardiology
Copyright © 2003, European Society of Cardiology
Of mice and men, rats and atherosclerosis
Department of Surgery, University of Alberta, 275 Heritage Medical Research Centre, Edmonton, Alberta, Canada T6G 2S2
jim.russell{at}ualberta.ca
* Tel.: +1-780-492-6359; fax: +1-780-492-1308.
Received 16 July 2003; revised 17 July 2003; accepted 20 July 2003
See article by Lyngdorf et al. [10] (pages 854–862) in this issue.
In less than 100 years, biology and medicine have been transformed by the effects of research that has eclipsed that of the 19th century in chemistry and that of the early half of the 20th century in physics. Whereas clinical research on human subjects has been important at the level of the application of knowledge at the bedside, the fundamental discoveries have been the result of basic science. Since the days of Harvey [1], real advances in the biomedical sciences have depended critically on the use of animals as models of human physiology, pathophysiology, and metabolism. Current animal models constitute technology that has been derived from scientific advances that, in turn, foster new scientific understanding and developments.
The widespread use of rodent models dates from seminal work at the Wistar Institute where, starting in 1906, Donaldson [2] established the rat as a defined animal model for the study of many aspects of physiology. As he pointed out, the rat has many similarities to humans and its rapid development makes the study of life cycle processes practical. It is also both small enough to be inexpensive to breed and house and large enough to allow many studies of physiology and metabolism that are difficult or impossible in smaller species. The development of the mouse came somewhat later, led by work at the Jackson Laboratory, and benefited greatly from new techniques in genetics.
The unraveling of the genetic code and development of molecular biology techniques have provided an enormous and continuing stimulus to biomedical research in recent decades. The ability to manipulate murine stem cells and to readily create knockout and transgenic mouse strains has resulted in great interest in genetically modified animals, especially in mice. In relative terms, there has been much less interest in rat models despite the large number of genetic models of disease developed through isolation of spontaneous mutations in various rat strains. It has not been possible to manipulate embryonic stem cells in the rat as readily and successfully as in the mouse. This has been a major factor in the reduced interest in the species, despite the successful creation of various transgenic rats. The relative balance between the mouse and the rat may be about to change again as Michael Gould and his coworkers [3] have now reported the creation of two related gene knockout strains of rat. Gould was prompted to use the rat to generate the knockout of the breast tumor suppressor genes Brca1 and Brca2 because tumors in the rat have a spectrum of hormonal responses that is similar to the human response. Their work opens the prospect of developing unique rat models based on genetic manipulation of the many existing disease models.
The apoE–/– (knockout) mouse was generated by gene targeting in embryonic stem cells and was reported by Piedrahita et al. [4] in 1992. This strain and other genetically modified mouse models for the study of atherosclerosis have become favored among lipid and lipoprotein investigators [5,6] although significant reservations remain among some in the pathology/pathophysiology area. A major, and little discussed, problem is that of the increasing evidence that disorders of lipid and lipoprotein metabolism are not the only cause of cardiovascular disease. Brown and Goldstein [7] claimed in 1996 that "Exploitation of recent breakthroughs—proof of the cholesterol hypothesis, discovery of effective drugs, and better definition of genetic susceptibility factors—may well end coronary disease as a major public health problem early in the next century". On the other hand, there is evidence that hypercholesterolemia (under the current definition) may underlie less than 40% of all cardiovascular disease [8] and that insulin resistance, hyperinsulinemia and type 2 diabetes are significant contributors to the remaining burden of the disease [9].
The apoE–/– mouse has been claimed to exhibit atherosclerosis throughout the major arteries [6], but the primary lesions seen and used as an experimental index are perivalvular lesions at the aortic root. These lesions are atherosclerosis-like, but are quite different from the raised intimal lesions seen in humans, cholesterol-fed rabbits, and some rat strains. Most of the areas described are essentially fatty streaks and thus could be categorized as pre-atherosclerotic lesions. The development of significant lesions in the apoE–/– mouse also requires cholesterol-supplemented diets, which introduces further variables and complications.
With growing understanding of the association between type 2 diabetes, the metabolic syndrome, and cardiovascular disease, attempts have been made to induce obesity and diabetes in the apoE–/– mouse. To date these have been unsuccessful, but the prospect of combining in one model the atherogenic propensities associated with a lipid disorder and with type 2 diabetes has remained attractive. In their paper, Lyngdorf et al. [10] report a successful approach to the creation of a hyperinsulinemic, type 2 diabetic apoE–/– mouse. The authors intended to use the model to investigate the interaction of the lipid dysfunction of the hypo-apoE status and the metabolic dysfunction of the type 2 diabetes on atherogenesis. The results obtained were paradoxical, showing reduced perivalvular lesion severity in the presence of hyperinsulinemia and diabetes. While these results represent a failure to create a new model of diabetes-related cardiovascular disease, they are an important contribution to the study of atherosclerosis, with major implications for the use of animal models of the complex disease process.
What are the implications of this study that, at a simplistic level, could be considered to have negative results? First, the study emphasizes, again, the complex nature of cardiovascular disease and the need for great care in characterizing animal models to ensure that their properties are effective analogues of those of humans with cardiovascular disease. Second, the apparently paradoxical findings are not inconsistent with other observations of significant differences between the metabolism of the mouse and that of humans. In this respect, the findings confirm the view that models such as the rat may be better for studying diseases related to human physiology and metabolism. This is so not only because of the larger size and ease of conducting experimental procedures, but because rats and humans share very similar environments and are omnivorous. Lastly, it may well be that reliance on animal strains with specific gene deletions such as the apoE–/– mouse needs to be approached with care. In many respects the spontaneous genetic mutations that underlie the many rat models of disease are better analogues of the genetic contributors to human disease propensities. An important reason is that they are often polygenetic, requiring a specific mutation on a particular genetic background for overt disease expression. The development of cardiovascular disease in humans with the metabolic syndrome varies among population groups in a similar manner [11].
The coming years will be exciting times in cardiovascular research, with the promise of developing an effective understanding of the causes of, and preventative strategies against, an expanding worldwide epidemic. The techniques developed to create the genetically modified mouse strains, both transgenic and knockout, offer the opportunity to modify the rat mutant models that mimic human disease and to unravel the complex origins of the end-stage disease. As shown by Gould’s group, extension of the techniques to the rat will greatly facilitate these approaches. Other new techniques, such as the gene chip, will also help identify candidate genes and pathways for such studies. Overall, these processes that are already underway offer the promise of precisely targeted therapeutic and treatment methods at the behavioral, dietary, and pharmacological levels.
 |
References |
|---|
 Top References |
|---|
- Frank R.G. Harvey and the Oxford physiologists: scientific ideas and social interaction. (1980) Berkeley, CA: University of California Press.
- Lindsay J.R. Historical foundations. In: The laboratory rat—Baker H.J., Lindsay J.R., Weisbroth S.H., eds. (1979) vol. I. Orlando, FL: Academic Press. 2–36.
- Zan Y., Haag J.D., Chen K.-S., et al. Production of knockout rats using ENU mutagenesis and a yeast-based screening assay. Nature Biotechnol (2003) 21:645–651.
- Piedrahita J.A., Zhang S.H., Hagman J.R., Oliver P.M., Maeda N. Generation of mice carrying a mutant apolipoprotein E gene inactivated by gene targeting in embryonic stem cells. Proc Natl Acad Sci USA (1992) 89:4471–4475.
- Tangirala R., Rubin E.M., Palinski W. Quantitation of atherosclerosis in murine models: correlation between lesions in the aortic origin and in the entire aorta, differences in the extent of lesions between sexes in LDL receptor-deficient and apolipoprotein E-deficient mice. J Lipid Res (1995) 36:2320–2328.
- Smith J.D., Trogan E., Ginsberg M., Grigaux C., Tian J. Decreased atherosclerosis in mice deficient in both macrophage colony-stimulating factor (op) and apolipoprotein E. Proc Natl Acad Sci USA (1995) 92:8264–8268.
- Brown M.S., Goldstein J.L. Heart attacks: gone with the century. Science (1996) 272:629.
- Ørnskov F. The cost effectiveness of simvastatin treatment to lower cholesterol in patients with coronary heart disease. In: Atherosclerosis XI. Proceedings of the XIth International Symposium on Atherosclerosis—Jacotot B., Mathé D., Fruchart J.-C., eds. (1998) Singapore: Elsevier. 925–932.
- Després J.-P., Lamarche B., Mauriège P., et al. Hyperinsulinemia as an independent risk factor for ischemic heart disease. New Engl J Med (1996) 334:952–957.
- Lyngdorf L.G., Gregersen S., Dauherty A., Falk E. Paradoxical reduction of atherosclerosis in apoE-deficient mice with obesity-related type 2 diabetes. Cardiovasc Res (2003) 59:854–862.
- Hegele R.A., Zinman B., Hanley A.J.G., et al. Genes, environment and Oji-Cree type 2 diabetes. Clin Biochem (2003) 36:163–170.
- Lindsay J.R. Historical foundations. In: The laboratory rat—Baker H.J., Lindsay J.R., Weisbroth S.H., eds. (1979) vol. I. Orlando, FL: Academic Press. 2–36.
CiteULike 
Connotea 
Del.icio.us What's this?
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||