Characteristics of WHHLCA and WHHLMI Rabbits, Animal Models for Hypercholesterolemia and Coronary Atherosclerosis, and the Use for Studies about Atheroma Stabilizing Effects of Hypolipidemic Drugs

Abstract

Patients with acute coronary syndromes (ACS), which include unstable angina, acute myocardial infarction, and sudden cardiac death, are estimated more than 20 million in the world. Pathological examinations have demonstrated that vulnerable coronary atheromatous plaque is important in the onset of ACS. However, the detail mechanism is still uncertain. Several clinical intervention trials have showed that statins, inhibitors of cholesterol biosynthesis, suppress the onset of ACS. On the other hand, in vitro studies suggested that statins suppressed smooth muscle cell (SMC) proliferation and induced the apoptosis, while SMC is important in stabilization of atheromatous plaque. Therefore, results of in vitro studies are contradictory to observation of clinical studies. To clarify the mechanism of ACS and preventive effects of statins on ACS, suitable animal models have been required. We developed coronary atherosclerosis-prone WHHLCA rabbits and myocardial infarction-prone WHHLMI rabbits by a technique of selective breeding and examined statins' effects on coronary atherosclerosis. The original WHHL rabbits showed hypercholesterolemia due to deficiency of the LDL receptors and aortic atherosclerosis while the coronary plaques were mild and the frequency was very low. WHHLCA rabbits were developed from the original WHHL rabbit and have advanced coronary plaques but incidence of myocardial infarction is very low. WHHLMI rabbits were developed from WHHLCA rabbits and the cumulative incidence of myocardial infarction is more than 90% at 30 months old. WHHLMI and WHHLCA rabbits closely resemble humans in the lipid metabolism and atherosclerosis although mice and rats are largely different. In WHHLCA and WHHLMI rabbits, the coronary atherosclerosis start to develop from 2 months old and becomes transitional lesions at about 10 months old. At above 20 months old, the coronary plaques become complicated lesions. In intervention studies using WHHLCA and WHHLMI rabbits, therefore, we start treatments from 10 months old for one year, and examined coronary plaques at the end of the experiment. This study design is compatible to human intervention treatments. As a result, statins prevent destabilization of coronary plaques due to depression of macrophages in the plaque. The results support the hypothesis derived from human clinical studies that statins would stabilize coronary plaques and stabilization of coronary plaque would be important to prevent ACS. In addition, our results also suggested that statins effects on arterial smooth muscle cells are very weak in vivo compared to in vitro studies. In conclusion, since WHHLCA and WHHLMI rabbits resemble humans in the characteristics of lipid metabolism and atherosclerosis, these rabbit strains are useful for studies of hypercholesterolemia, atherosclerosis, and development of hypolipidemic and anti-atherosclerotic drugs.