Atherosclerotic

Fibrous cap

Fibrous cap

Ca2+

Figure 72.1 Swine model of atherosclerosis. Histologic samples from normal and atherosclerotic pig arteries demonstrate the hallmark characteristics of atherosclerosis, including cholesterol deposition, calcification, foam cell accumulation, and development of a fibrous cap.

Ca2+

Figure 72.1 Swine model of atherosclerosis. Histologic samples from normal and atherosclerotic pig arteries demonstrate the hallmark characteristics of atherosclerosis, including cholesterol deposition, calcification, foam cell accumulation, and development of a fibrous cap.

development of mouse strains genetically modified by homologous recombination to develop accelerated atherosclerotic lesions, and was further cemented by the mouse genome project, which anointed the mouse as the primary model for genetic analyses in most laboratories today.

Although previous studies of strain-specific differences in medial thickening led to the supposition that mice are resistant to atherosclerosis, the development of hypercholesterolemic mice by deletion of the gene for apolipoprotein E indicated that this is not the case (Plump et al., 1992; Zhang et al., 1992). These mice become spontaneously hypercholesterolemic and develop athero-matous lesions in the aorta, along the aortic valves, and within the great vessels. The development of these lesions occurs spontaneously but can be markedly accelerated by feeding the mice a high-fat ("Western") diet. Acceleration of lesion formation with a high-fat diet can reduce the time needed for lesions to fully invest the large vessels in ApoE—/— mice to three months or less, which is one of the most rapid intervals among experimental models of atherosclerosis. Lesions form with many of the morphological characteristics of human atherosclerosis, and usually are quantified by serial sectioning at the level of the aortic valve or by Oil Red O staining of the aorta en face to define the extent of lesion formation throughout the aorta. Unfortunately, the distribution of lesions does not extend to the coronary circulation and advanced features such as plaque rupture are observed only under extraordinary circumstances.

ApoE—/— mice and the somewhat less frequently used but phenotypically similar LDL receptor-deficient mice are now the most common animal models of atherosclerosis by far. It is noteworthy that, to date, modulation of cholesterol metabolism has been the only mechanism that results in atheroma development in mice. The development of ApoE—/— mice has made possible an extraordinary analysis of modifiable factors such as diet, exercise, drug effects, and others that determine the extent of atherosclerotic lesion formation. In addition, the widespread availability, low cost, and rapid time to disease formation have made ApoE—/— mice an ideal model for drug screening and validation experiments.

In addition to these virtues, the availability of a broad variety of genetically modified mouse strains has allowed the molecular dissection of events that influence the pathogenesis of atherosclerosis that is virtually impossible in other models of this disease. The usual strategy has been to cross ApoE—/— mice with mice deficient in other proteins that are required for specific pathways or cellular events to determine the effects of this second molecule on the ApoE—/— phenotype. As an example of this approach, ApoE—/— mice also deficient in activity of the NADPH oxidase (by deletion of the essential component p47phox) have reduced levels of atherosclerosis, which indicates a necessary role for oxidative stress in atherosclerotic lesion formation (Barry-Lane et al., 2001).

This approach can be further augmented by bone marrow transplantation to dissect out the relative contributions of different cell types (circulating versus mural cells) to any phenotype that is observed. Finally, mice are perhaps the only animal model available in which it is feasible to perform advanced genetic crosses to search for new atherosclerosis-related genes and genetic modifiers that regulate the disease process through the awesome power of genetics.

Many of these features would suggest that ApoE—/— or similar mice are the ideal animal models for studying atherosclerosis, and in many respects they are. As indicated earlier, the availability, rapid time to disease onset, and genetic features are unique to this model, and no other model is as cost-effective on an animal-by-animal basis. Nevertheless, the limited distribution of lesions within the circulatory tree in this model and the failure to replicate many key steps in atherosclerotic vascular disease are important limitations. Thus, it is unlikely that mouse models alone will suffice in all circumstances for thorough evaluations of atherosclerotic disease.

Blood Pressure Health

Blood Pressure Health

Your heart pumps blood throughout your body using a network of tubing called arteries and capillaries which return the blood back to your heart via your veins. Blood pressure is the force of the blood pushing against the walls of your arteries as your heart beats.Learn more...

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