Morphological features of coronary plaques in WHHLMI rabbits (<i>Oryctolagus cuniculus</i>), an animal model for familial hypercholesterolemia

Abstract

Abstract:In order to examine their suitability for studies on coronary atherosclerosis, we evaluated the features of coronary atherosclerotic plaques in myocardial infarction-prone Watanabe heritable hyperlipidemic (WHHLMI) rabbits, a spontaneous animal model for coronary atherosclerosis and myocardial infarction. Coronary segments of the hearts of 187 WHHLMI rabbits (10-29 months old) were sectioned serially and stained histopathologically and immunohistologically. Progression of coronary lesions was prominent in rabbits that had died suddenly. The degree of coronary lesions of females was higher than that of males. Various types of atherosclerotic lesions were observed in the coronary arteries, such as plaques with a large lipid core covered by a thin fibrous cap, fatty streaks, early and advanced fibroatheromas, fibrous lesions, and advanced lesions with calcium accumulation and the vasa vasorum. In rabbits that had died suddenly, the frequencies of fibroatheromas or advanced lesions were higher than those of rabbits euthanized. Matrix metalloproteinase (MMP)-positive macrophages were detected in gaps among endothelial cells at the plaque surface, beneath the fibrous cap of thin-capped fibroatheromas, and at the bottom of the intimal plaques in which the tunica media was attenuated. Immunohistological results suggest that MMP-positive macrophages are involved in the initiation, progression, and destabilization of coronary plaques, in addition to vascular remodeling, even in WHHLMI rabbits. In conclusion, coronary lesions in WHHLMI rabbits resemble human atherosclerotic lesions, and thus, the WHHLMI rabbit is a suitable animal model for studies on human coronary plaques.

The History of the WHHL Rabbit, an Animal Model of Familial Hypercholesterolemia (I) - Contribution to the Elucidation of the Pathophysiology of Human Hypercholesterolemia and Coronary Heart Disease -

“…In the early stages of atherosclerosis, macrophages infiltrate into the arterial intima from the surface of the intima and the vasa vasorum in the deep intima. In WHHLMI rabbits, the vasa vasorum was observed with extracellular lipid deposits and macrophage accumulation in the deep area of advanced coronary lesions, in addition to the intimal surface 29) . Therefore, it should be noted that the pathogenesis of ath- Table 3.…”

“…Therefore, it should be noted that the pathogenesis of ath- Table 3. Characteristics of coronary lesions elucidated in studies using WHHL rabbit family • Differences between coronary artery lesions rich in fibers and aortic lesions rich in lipids 15,61) • The relevance of factors other than conventional risk factors (such as serum total cholesterol levels, HDL levels, oxidative stress, hyperglycemia, hypertension, and others) in the development and progression of coronary lesions 75) • Involvement of genetic factors different from aortic lesions in the development of coronary artery lesions 75) , and involvement of the coronary curvature in the progression and composition of lesions 68) • The relevance of additional factor(s) in the rupture of unstable coronary lesions characterized by thin-capped fibroatheroma 4,22,65) • Involvement of coronary spasm in rupture of coronary lesions and the occurrence of acute coronary syndromes 22,65) • The relevance of several serum lipid molecules identified with lipidome analyses in the development and progression of coronary lesions 75) • Involvement of macrophages infiltrated into the deep area of intima through vasa vasorum 29) in coronary outward remodeling 67) • Suppression and destabilization of atherosclerotic lesions by lowering serum lipid levels 5) human coronary lesions 30) , various types of coronary lesions were observed in WHHLMI rabbits (Fig. 3), such as fatty streak, fibrous lesion, fibroatheroma, thin-capped fibroatheroma, and advanced complicated lesions with reduced cellular components, calcification, vasa vasorum, etc.…”

“…3), such as fatty streak, fibrous lesion, fibroatheroma, thin-capped fibroatheroma, and advanced complicated lesions with reduced cellular components, calcification, vasa vasorum, etc. 22,23,29) . However, physiological intimal thickening in normal arteries observed in humans 30) was not observed in WHHLMI rabbits.…”

“…Coronary lesions of WHHLMI rabbits are initiated from fatty streaks, and then progress to fatty patches, atheroma, fibroatheroma, thin-capped fibroatheroma, and advanced complicated lesions with reduced cellular components, calcification, vasa vasorum, etc. 4,22,29) . These features of coronary lesions of WHHLMI rabbits resemble human atherosclerosis 30) .…”

The Coronary Artery Running Pattern is One of the Causes of Individual Differences in the Progression of Coronary Atherosclerosis in WHHLMI Rabbits, an Animal Model for Coronary Atherosclerosis

“…We previously reported that other factors than serum cholesterol levels may be related to the progression and composition of coronary lesions in WHHLMI rabbits 9 ) . The WHHLMI rabbit is an animal model for human familial hypercholesterolemia 10 ) and develops diffuse coronary lesions 9 , 11 ) even with normal chow feeding. The factors responsible for individual differences in the development of coronary lesions have yet to be identified.…”