Publication: Watanabe rabbits with heritable hypercholesterolaemia: a model of atherosclerosis
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Date
1998
Authors
Aliev, G. ; Burnstock, G.
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Publisher
Murcia : F. Hernández
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DOI
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info:eu-repo/semantics/article
Description
Abstract
Many factors play important roles in the
development of atherosclerotic lesions. The leading risk
factor for atherosclerosis is familial hypercholesterolaemia
(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 atherosclerosis
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 ulero.
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 p-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 hypercholesterolaemia.
Damage or loss of endothelial cells
can predispose the atherosclerotic vessels to vasospasm
and can leave vessels unprotected against vasoconstrictor
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.
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