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Watanabe rabbits with heritable hypercholesterolaemia: a model of
atherosclerosis
G. Aliev and G. Burnstock
Department of Anatomy and Developmental Biology, University
College London, London, UK
Offprint requests to: Pof.
G. Burnstock, Autonomic Neuroscience Institute, Royal Free Hospital School
of Medicine, Rowland Hill Street, London NW3 2PF, UK. FAX: 44-171-830-2949.
Summary. Many factors play
important roles in the development of atherosclerotic lesions. The leading
risk factor for atherosclerosis is familial hypercholester-olaemia (FH).
FH is a genetic disease characterized by a deficiency of receptors for low
density lipoprotein (LDL) on the plasmalemma of endothelial cells, a high
level of serum LDL, and early development of athero-sclerosis and skin xanthoma.
Watanabe and colleagues have developed a line of rabbits with unprovoked
hypercholesterolaemia, increased blood level of LDL, pronounced atherosclerosis
and skin xanthoma. These Watanabe Heritable Hyperlipidaemic (WHHL) rabbits
possess an inheritable mutation of one gene, similar to that in human FH.
The morphogenesis of atherosclerosis in patients with FH is characterized
by multifocal deposit of lipids in the stromal cells of thymus, spleen,
skin, interstitial and parenchymatous cells of kidneys and the presence
of some single foam cells in aorta. The manifestation of atherosclerotic
lesions in WHHL rabbits increases progressively with age but the presence
of atherosclerotic lesions in newborn WHHL rabbits suggest that the process
may commence in utero. Moreover, the main mass of plasma cholesterol in
WHHL rabbits is first found in LDL and to a lesser degree in lipoproteins
of intermediate density. This is contrary to diet-induced atherosclerosis
in rabbits where the main mass of serum cholesterol is found in very low
density b-lipoproteins. Thus the distribution of cholesterol among lipoprotein
fractions differs from that in WHHL rabbits. Atherosclerotic damage of arteries
in WHHL rabbits goes through several stages. During the progression of intimal
damage, lipid and foam cell deposits are found in the internal surface together
with developing plaques and increased content of lipids in the tunica media.
Calcification often follows this process. The main factors initiating atherosclerosis
in WHHL rabbits are adhesion of leukocytes and platelets to endothelial
cells and the accumulation of lipids in the aortic wall. The deposits of
lipids in macrophages and intimal smooth muscle cells in WHHL rabbits occurs
mostly at the expense of cytoplasmic neutral lipid particles with some accumulation
in lysosomes. Hypertension as a risk factor increases the area of atherosclerotic
damage in all arterial vessels in WHHL rabbits, particularly in the thoracic
and abdominal aorta. Morphogenesis of the development of atherosclerosis
in WHHL and diet-induced atherosclerosis in rabbits was similar, but differs
from rats with heritable hyper-cholesterolaemia. Damage or loss of endothelial
cells can predispose the atherosclerotic vessels to vasospasm and can leave
vessels unprotected against vaso-constrictor stimuli. The development of
the WHHL model has not only given insight into the mechanisms of development
of familial hypercholesterolaemia but has also provided a model for assessing
various therapeutic approaches for the prevention and treatment of atherosclerosis.
Histol. Histopathol. 13, 797-816 (1998)
Key words: Watanabe heritable
hyperlipidaemic rabbits, Aorta, Morphology, Endothelium, Atherosclerosis
DOI: 10.14670/HH-13.797
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