How Useful Are Mouse Models for Understanding Human Atherosclerosis?
Review Examines the Available Evidence
Animal models are critical for testing new research ideas and bringing them closer to the clinic, but too often observations seen in flies, rodents, and other organisms are later not apparent in humans or are present to a much lesser extent, stripping them of clinical relevance. A new Cell Metabolism review of >9000 publications in the mouse literature indicates that mouse models used for atherosclerosis research may be quite valuable, however, especially for revealing critical processes involved in atherogenesis.
“Over the past 30 years, the vast majority of mechanistic insights into atherosclerosis has come from studies in mice, and so a detailed analysis of the relevance of the findings is clearly important if the results are to be applied to the development of new therapies,” said Aldons J. Lusis, PhD, who is a Professor of Microbiology, Immunology, and Molecular Genetics at the David Geffen School of Medicine at UCLA and is the senior author of the review.
By examining the mouse literature, Lusis and his colleagues observed striking concordance of risk factors for atherosclerosis in mice and humans. These risks include dyslipidemia, systemic inflammatory disorders, exposure to cigarette smoke and air pollution, type 1 and type 2 diabetes mellitus, distress, kidney failure, obesity, and others.
The scientists also discovered a highly significant overlap of mouse genes with human genes identified by genome-wide association studies. Of the 46 genes that were strongly linked with coronary artery disease in studies conducted in mouse models, all but 1 exhibited consistent effects on atherosclerosis-related characteristics.
When the investigators compared 178 pathways from human genome-wide association studies associated with coronary artery disease with 263 from mouse studies, they found that >50% were consistent between both species.
Although mice offer a number of advantages, experts caution that a major limitation is their natural resistance to atherosclerosis. Mice develop atherosclerosis only when their cholesterol metabolism is genetically modified (eg, by low-density lipoprotein receptor or apolipoprotein E knockout). Researchers have noted that because mice lack the cholesteryl ester transfer protein, a carrier that facilitates the transport of cholesteryl esters and triglycerides among different lipoproteins, the animals usually have lower plasma cholesterol levels and different lipid metabolism compared with humans. Therefore, it is unclear whether genetically modified mice with high cholesterol can help to clarify the mechanisms leading to a common human disease such as atherosclerosis.
In addition, although the small size of mice results in more convenient use for experimentation, it also limits the ability to visualize and dissect the coronary arteries. Considerable differences are also evident in the anatomy and physiology of the cardiovascular system between mice and humans.
The review by Lusis and his colleagues indicates that, despite these limitations, mouse models of atherosclerosis are revealing important clinical insights relevant to humans. “Our analyses, based on comparisons of GWAS [genome-wide association studies] data with results of thousands of studies in mice, indicate that mouse models of atherosclerosis share many features with the human disease, including key genes, pathways, and environmental interactions,” said Lusis.
We are lacking a good model for studying the mechanisms of plaque rupture, however. “Mouse models rarely show evidence of lesion rupture, a very significant limitation since about three-quarters of heart attacks result from rupture followed by thrombosis,” said Lusis. “Whether robust mouse models of rupture can be developed is unclear—for example, the small size of mouse lesions may be a limiting factor. Nevertheless, the factors contributing to the stability of lesions have been successfully examined in mice, using the fibrous cap and extracellular matrix characteristics as surrogates.”
Moreover, genome-wide association study findings made in humans can be further examined in mice, which are suitable for targeted genetic manipulation. “Human association findings can be mechanistically explored in mice, which clearly increases the relevance of respective findings in mice for the development of human therapies,” said Heribert Schunkert, MD, who is a Professor of Cardiology at the Technical University of Munich in Germany and a coauthor of the review.
Lusis, Schunkert, and their coauthors noted that, because shortcomings exist to research using knockout mice that model subtle genetic variations as well as experiments conducted on mouse strains with a single genetic background, focusing on pathogenic pathways rather than individual genes will likely be a more productive strategy for studying mouse models of human disease. Determining the factors that regulate these pathways and identifying the tissues in which they contribute to atherosclerosis are top priorities for cardiovascular researchers.
Circulation is available at http://circ.ahajournals.org.
- © 2017 American Heart Association, Inc.