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Coronary and aortic atherosclerosis in WHHL rabbits, an animal model of familial hypercholesterolemia
WS5-K-3-01
C O R O N A R Y AND A O R T I C A T H E R O S C L E R O S I S HYPERCHOLESTEROLEMIA M. Shiomi, T. Ito, and T. Yata Institute for E x p e r i m e n t a l Animals, Japan
IN WHHL
Kobe
RABBITS,
University
AN A N I M A L
School
of
MODEL
OF F A M I L I A L
Medicine,
Kobe,
The Watanabe heritable hyperlipidemic (WHHL) r a b b i t is a strain with hypercholesterolemia and atherosclerosis due to genetic deficiency of low density lipoprotein receptors. This rabbit strain was established at 1979 by inbreeding from a mutant discovered in 1973 at Kobe University. The incidence of coronary atherosclerosis was markedly l o w i n WHHL r a b b i t s born between 1973 and 1 9 8 0 . We h a v e c a r r i e d out selective breeding experiments after 1980 to increase the incidence of coronary atherosclerosis. During these experiments, we f o u n d that coronary atherosclerosis was different from aortic atherosclerosis. Heritability of atherosclerosis was examined by analyzing the relationship between atherosclerosis in parents and their offspring, The frequency of offspring with severe coronary stenosis born by the parents with severe lesions was about 3 times high compared to the offsprings derived from the parents with mild lesions. To e x a m i n e the effect of lipoprotein on a t h e r o s c l e r o s i s , the serum lipoprotein was fractionated by ultracentrifuge or polyacrylamide gel electrophoresis (PAGE). Aortic atherosclerosis was significantly related to cholesterol/triglyceride ratio in very low density lipoprotein, while coronary atherosclerosis was significantly related to midband detected b y PAGE. To examine histopathological difference between coronary and aortic atherosclerosis, atherosclerotic lesions were immunohistochemically and conventionally stained and the area of the each component was measured by a color image analyzer. The percent macrophage area in coronary lesions was significantly low compared to aortic lesions, while the percent of smooth muscle cell area and collagen area were significantly higher in coronary lesions. We concluded that: 1) c o r o n a r y atherosclerosis was heritable: 2) t h e r i s k factors related to coronary atherosclerosis was different from those related to aortic atherosclerosis; 3) l e s i o n a l composition of coronary atherosclerosis was different from that of aortic atherosclerosis.
WS5-K-3-02
AUGMENTEDRESPONSESTO VASOCONSTRICTORSTIMUUAND REDUCEDENDOTHEUUM-DEPENDENTVASORELAXATION IN AORTASFROMWHHL RABBITS
S. Kawashima, K. Hirata, Y. Miwa, M. Suematsu, M. Yokoyama. First Dept. of Internal Medicine, Kobe Univ. School of Medicine We studied the alterations in vascular responsiveness to vasoconstrictor substances and endothelium-dependent vasodilatory substances (EDVS) in aortas of Watanabe heritable hyperlipidemic (WHHL) rabbits. Strip preparations of isolated thoracic aortas from normal and WHHL rabbits were suspended in organ baths for isometric tension measurements. The endothelium-dependent vasorelaxation to acetylcholine (ACh), ADP, and A23187 was reduced and vasoconstrictor responses to ergonovine and serotonin (5-HT) was augmented in WHHL rabbits compared with agematched control rabbits. In contrast, vasodilatory responses to endothelium-independent vasodilatory substances such as nitroglycerine and Isoproterenol and vasoconstriction by phenylephrine were not different between control and WHHL rabbits. Vasodilatory response to ACh decreased progressively in proportion to the degree of atherosclerosis progression. Since 5-HT also produces EDRF, the hyperreactivity of the vessel of WHHL rabbit to 5-HT is likely related to both the reduced endothelium-dependent vasodilation and augmented vasoconstriction. To clarify the mechanisms of the hyperreactivity to 5-HT in atherosclerotic artery, we simultaneously measured changes in intracellular Ca2+ concentration and isometric force in vascular smooth muscle. In spite of the hyperreactitivity to 5-HT, Ca2+ sensitivity of contractile element to 5-HT was not augmented in WHHL rabbits. Therefore, the hyperreactivity to 5-HT is likely due to the increased number of 5-HT receptors and/or augmentation of signal transduction system. These alteration of vascular responsiveness to vasoconstrictor stimuli and EDVS may play a significant role in the pathogenesis of vasospasm.
359
C O R O N A R Y AND A O R T I C A T H E R O S C L E R O S I S HYPERCHOLESTEROLEMIA M. Shiomi, T. Ito, and T. Yata Institute for E x p e r i m e n t a l Animals, Japan
IN WHHL
Kobe
RABBITS,
University
AN A N I M A L
School
of
MODEL
OF F A M I L I A L
Medicine,
Kobe,
The Watanabe heritable hyperlipidemic (WHHL) r a b b i t is a strain with hypercholesterolemia and atherosclerosis due to genetic deficiency of low density lipoprotein receptors. This rabbit strain was established at 1979 by inbreeding from a mutant discovered in 1973 at Kobe University. The incidence of coronary atherosclerosis was markedly l o w i n WHHL r a b b i t s born between 1973 and 1 9 8 0 . We h a v e c a r r i e d out selective breeding experiments after 1980 to increase the incidence of coronary atherosclerosis. During these experiments, we f o u n d that coronary atherosclerosis was different from aortic atherosclerosis. Heritability of atherosclerosis was examined by analyzing the relationship between atherosclerosis in parents and their offspring, The frequency of offspring with severe coronary stenosis born by the parents with severe lesions was about 3 times high compared to the offsprings derived from the parents with mild lesions. To e x a m i n e the effect of lipoprotein on a t h e r o s c l e r o s i s , the serum lipoprotein was fractionated by ultracentrifuge or polyacrylamide gel electrophoresis (PAGE). Aortic atherosclerosis was significantly related to cholesterol/triglyceride ratio in very low density lipoprotein, while coronary atherosclerosis was significantly related to midband detected b y PAGE. To examine histopathological difference between coronary and aortic atherosclerosis, atherosclerotic lesions were immunohistochemically and conventionally stained and the area of the each component was measured by a color image analyzer. The percent macrophage area in coronary lesions was significantly low compared to aortic lesions, while the percent of smooth muscle cell area and collagen area were significantly higher in coronary lesions. We concluded that: 1) c o r o n a r y atherosclerosis was heritable: 2) t h e r i s k factors related to coronary atherosclerosis was different from those related to aortic atherosclerosis; 3) l e s i o n a l composition of coronary atherosclerosis was different from that of aortic atherosclerosis.
WS5-K-3-02
AUGMENTEDRESPONSESTO VASOCONSTRICTORSTIMUUAND REDUCEDENDOTHEUUM-DEPENDENTVASORELAXATION IN AORTASFROMWHHL RABBITS
S. Kawashima, K. Hirata, Y. Miwa, M. Suematsu, M. Yokoyama. First Dept. of Internal Medicine, Kobe Univ. School of Medicine We studied the alterations in vascular responsiveness to vasoconstrictor substances and endothelium-dependent vasodilatory substances (EDVS) in aortas of Watanabe heritable hyperlipidemic (WHHL) rabbits. Strip preparations of isolated thoracic aortas from normal and WHHL rabbits were suspended in organ baths for isometric tension measurements. The endothelium-dependent vasorelaxation to acetylcholine (ACh), ADP, and A23187 was reduced and vasoconstrictor responses to ergonovine and serotonin (5-HT) was augmented in WHHL rabbits compared with agematched control rabbits. In contrast, vasodilatory responses to endothelium-independent vasodilatory substances such as nitroglycerine and Isoproterenol and vasoconstriction by phenylephrine were not different between control and WHHL rabbits. Vasodilatory response to ACh decreased progressively in proportion to the degree of atherosclerosis progression. Since 5-HT also produces EDRF, the hyperreactivity of the vessel of WHHL rabbit to 5-HT is likely related to both the reduced endothelium-dependent vasodilation and augmented vasoconstriction. To clarify the mechanisms of the hyperreactivity to 5-HT in atherosclerotic artery, we simultaneously measured changes in intracellular Ca2+ concentration and isometric force in vascular smooth muscle. In spite of the hyperreactitivity to 5-HT, Ca2+ sensitivity of contractile element to 5-HT was not augmented in WHHL rabbits. Therefore, the hyperreactivity to 5-HT is likely due to the increased number of 5-HT receptors and/or augmentation of signal transduction system. These alteration of vascular responsiveness to vasoconstrictor stimuli and EDVS may play a significant role in the pathogenesis of vasospasm.
359