Atherosclerosis in the Apolipoprotein E–Deficient Mouse

Abstract

Abstract-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 (apoEϪ/Ϫ) 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. The apoE-deficient (apoEϪ/Ϫ) mouse was created practically simultaneously in two separate laboratories, through gene inactivation by targeting. On a chow diet, the mice demonstrated a total cholesterol level Ͼ500 mg/dL, mostly in the VLDL and chylomicron remnant fractions. A Western diet quadrupled these fractions. 4,5 The apoEϪ/Ϫ mice available today through The Jackson Laboratories are descendants of the original apoEϪ/Ϫ mouse created by the Maeda group (t002052 B6.129P2-Apoetm1Unc). Plaque Pathology in the ApoE؊/؊ MouseFatty streaks were first observed in the proximal aorta of a chow-fed, 3-month-old mouse. 4 On this diet, as early as 10 weeks of age, foam cell lesions were observed by light microscopy. Intermediate lesions containing foam cells and smooth muscle cells were seen at 15 weeks, and fibrous plaques appeared at 20 weeks of age. A Western diet accelerated the process. Histological and morphometric analyses of plaque progression revealed an increase in complexity as well as in lesion size with age ( Figure 1). 6 Although molecular studies of vascular remodeling in these mice had not yet begun, fragmentation of the elastic lamina was well documented, as were calcification and wall thinning in most mice aged at least 32 weeks.Once the presence of plaques resembling human lesions was confirmed, there ensued explosive use of the model in the study of factors affecting plaque size and composition. Two quantitation methods are used extensively to measure plaques. The first measures plaque cross sectional area in slices taken at the level of the aortic sinus, 1 and is useful for mild or early stage disease. The second (increasingly popular) "en face" method involves pinning out the aorta and quantifying lesion area as a percentage of total surface area. 5,7 This method requires older mice, as it appears to be generally agreed on that plaques first appear proximally and only later appear distally. 6,8 Because there is no map of lesion appear-

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“…ApoAI normally is associated with HDL particles but has been observed on TG-rich lipoproteins in the genetic absence of apoE. ApoE plays a multifunctional role in intravascular and cellular lipid metabolism, primarily as a ligand for the seven identified members of the LDL receptor family and for cell surface heparin proteoglycans (31,32). Although apoE is expressed throughout the body, circulating apoE largely originates from the liver, where both newly synthesized and recycled apoE is secreted (33).…”

Inflammation contributes to the atherogenic role of intermittent hypoxia in apolipoprotein-E knock out mice

“…foam cells and smooth muscle cells appear at 15 weeks, and fibrous plaques at 20 weeks of age 16 . Western dyslipidemic diet accelerates this process and exacerbates plasma cholesterol levels.…”

Microarray gene profiling of laser-captured cells: A new tool to study atherosclerosis in mice

“…Genetically modified mouse models with increased susceptibility to atherosclerosis, such as the apolipoprotein E-deficient mice (apoE −/− ) mice, are an excellent tool to study the pathophysiology of atherogenesis and to test novel treatments [2][3][4]. There is substantial similarity in the histopathology of atheromatous lesions in apoE −/− mice and in humans, but the time span needed to observe significant progression is weeks to months in these mice as compared with decades in people [4,5].…”