Roles of the WHHL rabbit in translational research on hypercholesterolemia and cardiovascular diseases

Abstract

Conquering cardiovascular diseases is one of the most important problems in human health. To overcome cardiovascular diseases, animal models have played important roles. Although the prevalence of genetically modified animals, particularly mice and rats, has contributed greatly to biomedical research, not all human diseases can be investigated in this way. In the study of cardiovascular diseases, mice and rats are inappropriate because of marked differences in lipoprotein metabolism, pathophysiological findings of atherosclerosis, and cardiac function. On the other hand, since lipoprotein metabolism and atherosclerotic lesions in rabbits closely resemble those in humans, several useful animal models for these diseases have been developed in rabbits. One of the most famous of these is the Watanabe heritable hyperlipidemic (WHHL) rabbit, which develops hypercholesterolemia and atherosclerosis spontaneously due to genetic and functional deficiencies of the low-density lipoprotein (LDL) receptor. The WHHL rabbit has been improved to develop myocardial infarction, and the new strain was designated the myocardial infarction-prone WHHL (WHHLMI) rabbit. This review summarizes the importance of selecting animal species for translational research in biomedical science, the development of WHHL and WHHLMI rabbits, their application to the development of hypocholesterolemic and/or antiatherosclerotic drugs, and future prospects regarding WHHL and WHHLMI rabbits.

Figure 1

Changes in the serum lipid levels of WHHLMI rabbits with age (a), and the distribution of cholesterol in lipoproteins (b). Data are represented as the mean ± standard error of the mean. The serum cholesterol levels at 12 months old were about 900 mg/dL. Excess LDL cholesterol is atherogenic and HDL has antiatherogenic function. In WHHL rabbits, LDL is accumulated in the plasma and HDL-cholesterol is low, less than 20 mg/dL. The serum cholesterol levels decrease gradually with aging.

Figure 2

Development of atherosclerotic lesions in WHHLMI rabbits with age. The solid line denotes the degree of coronary atherosclerosis shown as coronary cross-sectional narrowing; lesion areas/area surrounded by the internal elastic lamina ×100 (%). The dotted line denotes the degree of aortic atherosclerosis; sum of the surface areas of the lesion/total surface area of the aortic lumen ×100 (%). Modified from Shiomi and Ito [8].

Figure 3

Features of the WHHLMI rabbit resembling humans and applicable translational research fields.