Mouse as a Crucial Animal Model of Atherosclerosis

Dear Colleagues,

Mice are highly resistant to atherosclerosis. The only exception in mice is the C57BL/6 strain. When fed a very high cholesterol diet containing cholic acid, however, the vascular lesions in the C57BL/6 differ from the human condition in the histologic nature and location, which is possibly attributed to a chronic inflammatory state rather than a genetic predisposition.

ApoE Knockout Mice—A Breakthrough

It has been a longstanding goal of many investigators around the world to create more effective mouse models for lipoprotein disorders and atherosclerosis and to identify genes that may modify atherogenesis and lesion progression. In 1992, apoE-deficient mice were generated by inactivating the ApoE gene through targeting.

The complexity of lesions in the apoE-deficient mouse, together with the benefits of using the mouse as a model of human disease, made it a desirable system in which to study both environmental and genetic determinants of atherosclerosis.

Hayek et al. developed a "western-type" diet for mouse studies, which is similar in composition to an average American diet of several years ago, consisting of 21% fat by weight, 0.15% cholesterol, and no cholic acid. When fed this diet, wild-type mice have a two-fold elevation in plasma cholesterol, while apoE-deficient mice have over a three-fold elevation to about 2000 mg/dl, again, mostly in βVLDL, but also in LDL.

LDL-Receptor-Deficient Mice

Gene targeting in embryonic stem cells has been also used to create LDL-receptor-knockout (LDLR-KO) mice, a model of familial hypercholesterolemia.

These mice have a more modest lipoprotein abnormality than the apoE-deficient mice, with increases in LDL and VLDL cholesterol leading to a total plasma cholesterol of about 250 mg/dl on a chow diet. On this diet, and at that level of plasma cholesterol, LDL receptor-deficient mice do not get atherosclerosis. However, this is a very diet-responsive model.

ApoE- and LDL-Receptor (LDLr) Double-Knockout (apoE/LDLr-DKO) Mice

This is a new mouse model that develops severe hyperlipidemia and atherosclerosis. It has been reported that, even on a regular chow diet, the progression of atherosclerosis is usually more marked in apoE/LDLr-DKO mice than in mice deficient for apoE alone. Thus, the apoE/LDLr-DKO mouse is a suitable model in which to study the anti-atherosclerotic effect of compounds without having to feed the animals an atherogenic diet.

A lot of crucial scientific research has been carried out using the above models. We would like to present the newest data about this very important field of atherogenesis research.

Dr. Jacek Jawien
Guest Editor

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