Mouse models of experimental atherosclerosis (original) (raw)
Related papers
The results in rodent models of atherosclerosis are not interchangeable
Atherosclerosis, 2007
The determinant factors for the development of atherosclerosis in response to dietary cholesterol were examined in two animal models to assess the comparability of results. We studied 128 male Apo E −/− and 128 LDLr −/− mice randomly assigned to baseline (n = 8) and 5 groups (n = 24 each) that differed only in their dietary fat and cholesterol supplements. At 10, 16, 24 and 32 weeks of age, 8 animals from each group were sequentially sacrificed and the variables analyzed. The lesion sizes changed at different rates but they were predictable and did not differ in complexity. We observed, however, significant differences between strains, particularly in the constitutive expression of liver genes, their metabolic response to dietary cholesterol, their feeding behaviour, their glucose tolerance and the gain in body weight. Both strains presented characteristics that resemble steatohepatitis but manifestations were more severe in LDLr −/− mice. The divergent responses indicate that the choice of the diet and the model should be carefully considered in atherosclerosis studies and extrapolations interpreted with caution.
Atherosclerosis in the Apolipoprotein E–Deficient Mouse
Arteriosclerosis, Thrombosis, and Vascular Biology, 2004
Arguably the most critical advancement in the elucidation of factors affecting atherogenesis has been the development of mouse models of atherosclerosis. Among available models, the apolipoprotein E–deficient (apoE−/−) mouse is particularly popular because of its propensity to spontaneously develop atherosclerotic lesions on a standard chow diet. A Medline search reveals over 645 articles dedicated to studies using this reliable and convenient “super” animal model since its inception (Piedrahita JA et al, Proc Natl Acad Sci U S A 1992;89:4471–4475; Plump AS et al, Cell 1992;71:343–353) with a more or less steady increase from year to year. This review will examine our present understanding of the pathology and progression of plaques in this animal and highlight some of the nutritional, pharmacological, and genetic studies that have enhanced this understanding.
Mouse models for atherosclerosis and pharmaceutical modifiers
Arteriosclerosis, …, 2007
Atherosclerosis is a multifactorial highly-complex disease with numerous etiologies that work synergistically to promote lesion development. The ability to develop preventive and ameliorative treatments will depend on animal models that mimic the human subject metabolically and pathophysiologically and will develop lesions comparable to those in humans. The mouse is the most useful, economic, and valid model for studying atherosclerosis and exploring effective therapeutic approaches. Among the most widely used mouse models for atherosclerosis are apolipoprotein E-deficient (ApoE Ϫ/Ϫ ) and LDL receptor-deficient (LDLr Ϫ/Ϫ ) mice. An up-and-coming model is the ApoE*3Leiden (E3L) transgenic mouse. Here, we review studies that have explored how and to what extent these mice respond to compounds directed at treatment of the risk factors hypercholesterolemia, hypertriglyceridemia, hypertension, and inflammation. An important outcome of this survey is that the different models used may differ markedly from one another in their response to a specific experimental manipulation. The choice of a model is therefore of critical importance and should take into account the risk factor to be studied and the working spectrum of the compounds tested.
Assessment of Unstable Atherosclerosis in Mice
Arteriosclerosis, Thrombosis, and Vascular Biology, 2007
There is an urgent need for representative animal models where prospective examination of the events leading up to plaque rupture and the rupture process itself can be performed. Recently, reports have begun to emerge that apolipoprotein E and low density lipoprotein receptor knockout mice may spontaneously develop unstable atherosclerosis, with plaques in certain parts of the arterial tree showing features suggestive of plaque rupture. Here we discuss the problems inherent in applying definitions of plaque rupture as seen in human arteries to mice; the anatomic locations in mice where unstable plaques do and do not occur; methods of inducing plaque instability in mice; and how to assess plaque stability in mice. These considerations lead us to a number of general recommendations. (Arterioscler Thromb Vasc Biol. 2007;27:714-720.)
Central European Journal of Immunology, 2012
Based on the current knowledge it is well ascertained that inflammation backgrounds the pathogenesis of atherosclerosis. Still, some open questions remain. Animal model is an important tool to study atherogenesis. Nowadays, genetically modified mice play a pivotal role. Wild mice are highly resistant to atherosclerosis, whereas “gene-targeted” modified mice can spontaneously (even without use of high cholesterol diet) develop atherosclerosis. The best example are apolipoprotein E (apoE)-knockout mice. In this review we will discuss usefulness of apoE-knockout mice to study the pathogenesis of atherosclerotic lesions, especially the immune mechanisms of atherogenesis.
Acta Angiologica, 2009
Although atherosclerosis was previously thought to be primarily a degenerative disease, it is now well ascertained that its pathogenesis is inflammatory. This review describes the history of the new atherogenetic concept, including the pivotal role of apoE-knockout mice in understanding the inflammatory background of atherosclerosis. The pivotal stage of atherogenesis is antigen presentation by macrophages to T lymphocytes. This antigen could be a fragment of oxidized LDL"digested" by macrophage, heat shock protein 60, b2 glycoprotein I, or fragments of bacterial antigens. During interaction between these cells, an immunological response of type T helper 1 (cellular) or T helper 2 (humoral) arises. Th1 response and its mediators: (IFN-g, TNF-a, interleukin 1, interleukin 12, and interleukin 18) increase atherogenesis, whereas Th2 response and its mediators: (interleukin 4, interleukin 5, and interleukin 10) decrease the development of atherosclerosis. The concept of atherosclerosis as an inflammatory disease is quite fresh; however, it is already considered an undisputable achievement of science, bringing particular therapeutic consequences. Since inflammation plays an important role in atherogenesis, during recent years it has become apparent that the 5-lipoxygenase (5-LO) pathway may play an important role in modifying the pathogenesis of atherosclerosis. These data raised the possibility that antileukotriene drugs may be an effective treatment regimen in atherosclerosis. In fact, we have found that among apoE and LDLR-double knockout mice the inhibition of FLAP, as well as cysteinyl leukotriene receptor blockade, was able to significantly prevent the development of atherosclerosis in gene-targeted mice.
Clínica e Investigación en Arteriosclerosis, 2016
The objective of this study is to explore the longitudinal progression of atherosclerosis and the correlation between methods to measure the lesion in apolipoprotein E-deficient mice. Atherosclerosis progression was assessed by measurements of foam cell-rich depositions in their proximal aortas, and/or in surgically excised arteries, to assess the histological luminal narrowing. A longitudinal study was performed by comparing the values for carotid, aorta, and femoral and iliac arteries using common histological techniques. There were no significant differences in progression between different arteries, but correlation with the classical measurement of atherosclerosis in the aortic root was poor. Each laboratory requires specific standardization. Carotid arteries were sensitive to atherosclerosis in these mice, and progression was exponential. In conclusion, morphometric data show the importance of the choice of the duration of treatment, the appropriate controls, and the age at which to begin the experiments.
Low-Cholesterol and High-Fat Diets Reduce Atherosclerotic Lesion Development in ApoE-Knockout Mice
Arteriosclerosis, Thrombosis, and Vascular Biology, 1999
We have investigated the effect of most common oils used in human nutrition on the development of atherosclerosis in apoE-knockout mice. Seven groups of animals, separated according to sex, were fed for 10 weeks either chow diet or the chow diet 10% (wt/wt) enriched with different oils (palm, coconut, 2 types of olive oil, and 2 types of sunflower oil) without addition of cholesterol. At the end of this period, plasma lipid parameters were measured and vascular lesions scored. None of the diets induced changes in plasma cholesterol concentrations, whereas plasma triglycerides were uniformly reduced in all diet groups. Some diets caused significant reductions in the size of atherosclerotic lesions in males and others in females; males responded most to sunflower oils and females to palm oil and one olive oil (II). The lesion reduction in males consuming sunflower oils was associated with the decrease of triglycerides in triglyceride-rich lipoproteins, whereas the decrease in females consuming olive oil II or palm oil was accompanied by an increase in plasma apoA-I. The increase in plasma apoA-I in the latter condition, is mainly due to overexpression of hepatic message elicited by a mechanism independent of apoE ligand. The data suggest that the different diets modulate lesion development in a gender specific manner and by different mechanisms and that the development of atherosclerosis, due to genetic deficiencies, may be modulated by nutritional maneuvers that may be implemented in human nutrition.