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Polygenic variation in hypercholesterolemia and coronary atherosclerosis in swine
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Monday 10 October 1994: Workshop Abstracts Wl ANIMAL MODELS OF ATHEROSCLEROSIS Polygenic variation in hypercholesterolemia and coronary atherosclerosis in swine m*, Hasler-Rapacz J, Reed J*, Rapacz J, *Phannuceuticals Division, Ciba Corp., Summit, NJ 07901, and Dept. of Generics, Univ. of Wisconsin, WI 53706, USA
We previously reported the spontaneous development of hypercholesterolemia and advanced coronary atherosclerosis in the Familial Hypercholesterolemic (FHC) strain of swine. FHC swine exhibit elevations in total cholesterol, LDL and apo B and develop stenotic coronary lesions which resemble advanced human plaques. Coronary lesions contain fibrous caps, necrotic cores, cholesterol clefts, calcification, neovascularization, and hemorrhage. FHC was first identified in swine bearing the Apo B mutant allele, LpbS. Recent studies, however, demonstrated that neither spontaneous hypercholesterolemia nor the development of coronary artery disease occurred exclusively in animals bearing the Lpb5 allele, demonstrating the polygenic nature of disease development. Selected breeding has allowed identification of a new cholesterol subphenotype in which LDL, triglycerides and the apolipoproteins B, C-III and E are elevated and HDL and Apo A-I are decreased. Such animals develop advanced coronary atherosclerosis as early as 14 months of age. Furthermore, as these pigs age, plaque hemorrhage, fissuring, ischemia and myocardial infarction are commonly observed. Development of advanced coronary artery disease with ischemia and myocardial infarction has previously only been reported in animal models employing the combination of vascular injury and cholesterol-enriched diet. Thus the FHC swine represent a unique model for the study of coronary artery disease. If efforts to down-size these swine are successful, they could also provide a valuable model in which to study restenosis. They also show promise as a model for testing hypolipidemics. Treatment with fenofibrate (45 mg/kg) for 3 weeks resulted in significant reductions in total cholesterol (26%), LDL (25%), apo B (24%) and triglycerides (36%). The hyperlipidemit and diabetic hamster, a novel animal model Simionescu M, Popov D, w, Hasu M, Costache G, Faiter S, Vulpanovici A, Stancu C, Simionescu N, Inst. of Cellular Biol. and Pathol., 8 B.P. Hasdeu Str., Bucharest-79691,
Romania
The purpose of these studies was to develop an animal model for investigating the pathobiochemical events that underline diabetes complicated with accelerated atherosclerosis. 180 Golden Syrian male hamsters were brought to three experimental conditions: streptozotocin-induced diabetes, diet-induced hyperlipidemia, and a combination of the above two perturbations, concomitantly or successively induced. At time intervals ranging from 2 to 26 weeks, the animals were examined for changes in some plasma constituents and ultrastmctural modifications of relevant tissues. Regardless of the timing of their combination, experimental diabetes and atherosclerosis were manifested by pronounced plasma alterations e.g. increase in cholesterol, apolipoprotein B and peroxides, glycation of LDL and of albumin, and the appearance of irreversibly glycated albumin. These coexisted with micro- and macroangiopathic lesions characteristic of each of these abnormalities, i.e. capillary narrowing and thickening of their basal laminae, proliferation of extracellular matrix (retina, glomeruli, myocardium), intimal accumulation of modified lipoproteins and
macrophage-derived foam cells in the aorta, coronaries and cardiac valves, leading to formation of atherosclerotic plaques. With time, the latter develop cholesterol crystals and a necrotic core. Remarkably, in diabetes alone, although the level of plasma cholesterol was not significantly affected, there was an increase in plasma peroxides and in triglyceride-rich VLDL associated with the development of atherosclerotic plaques, predominantly of fibrolipid type. This demonstrates that diabetic alterations of the arterial walls predisposes to accelerated atherogenesis in a sequence of cellular and biochemical events easily identifiable in the diabetic-athero hamster model. Lessons derived for haman atherosclerosis from the study of the WIUIL rabbit. Tanaka M, Otani H, Yokode M, Dept. of Geriatric Med., m, Faculty of Med., Kyoro University, 54 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto 606-01. Japan
The Watanabe heritable hyperlipidemic (WI-U-IL) rabbit has a genetic defect that is identical to that of familial hypercholesterolemia (FH) in humans. In the homozygous form, this defect leads to a nearly complete deficiency of LDL receptors. As a result, the plasma level in these rabbits is elevated lO-20-fold above normal. LDL deposits and is oxidatively modified in the arterial wall, producing xanthoma and atheromas, as in FH patients. Therefore, we can use WHHL rabbits as animal models for studying human FH. So far we demonstrated that the decreased hepatic LDL receptors elevate LDL particles by overproduction and undercatabolism of LDL particles in blood. In this study, we asked whether the production and secretion of apo B-containing lipoprotein is different between normal and WHHL rabbits, and found that it is not. The content of cholesteryl ester in the hepatocytes regulates the degradation of apo B protein itself. Even if LDL receptors are not available in WHHL rabbit hepatocytes, LDL cholesterol accumulates via a non-LDL receptor pathway. Therefore, as long as the hepatic content of cholesteryl ester in WHHL rabbits is the same as that of normal rabbits, production and secretion of apo B- containing lipoproteins is similarly regulated. A new rabbit model of atherosclerosis wJH, Fennessy PA, MandersonJA, Campbell GR, Centre for Research in Vascular Biology, Dept. of Anatomical Sciences, Univ. of Queensland, Brisbane, QLD 4072 Australia
In humans, atherosclerosis develops in those arteries which have pre-existing myointimal thickenings either diffusely along the vessel or as ‘intimal cushions’ at branch points. These thickenings begin to develop shortly after birth, and by the second decade of life diffuse intimal thickenings can be up to five times the thickness of the media in vessels such as the left descending coronary artery. Atherosclerosis rarely develops in vessels where the endothelium lies directly on the internal elastic lamina. Therefore, in order to model as closely as possible the human disease, the right carotid artery of the rabbit was de-endothelialized with a 2F Fogarty balloon catheter. This resulted in smooth muscle cells from the inner part of the media undergoing phenotypic change characterized by a decrease in the volume fraction of myofilaments (Vvmyo) from 67.9 + 3.6% to 42.7 f 3.38, followed by migration through fenestrations in the internal elastic lamina, and proliferation. During the development phase of the thickening (the first 2 weeks) the Vvmyo of the smooth muscle cells was low (38.8 + 1.0%). However, after 6 weeks this started to increase
Atherosclerosis X, Montreal, October 1994
Monday 10 October 1994: Workshop Abstracts Wl ANIMAL MODELS OF ATHEROSCLEROSIS Polygenic variation in hypercholesterolemia and coronary atherosclerosis in swine m*, Hasler-Rapacz J, Reed J*, Rapacz J, *Phannuceuticals Division, Ciba Corp., Summit, NJ 07901, and Dept. of Generics, Univ. of Wisconsin, WI 53706, USA
We previously reported the spontaneous development of hypercholesterolemia and advanced coronary atherosclerosis in the Familial Hypercholesterolemic (FHC) strain of swine. FHC swine exhibit elevations in total cholesterol, LDL and apo B and develop stenotic coronary lesions which resemble advanced human plaques. Coronary lesions contain fibrous caps, necrotic cores, cholesterol clefts, calcification, neovascularization, and hemorrhage. FHC was first identified in swine bearing the Apo B mutant allele, LpbS. Recent studies, however, demonstrated that neither spontaneous hypercholesterolemia nor the development of coronary artery disease occurred exclusively in animals bearing the Lpb5 allele, demonstrating the polygenic nature of disease development. Selected breeding has allowed identification of a new cholesterol subphenotype in which LDL, triglycerides and the apolipoproteins B, C-III and E are elevated and HDL and Apo A-I are decreased. Such animals develop advanced coronary atherosclerosis as early as 14 months of age. Furthermore, as these pigs age, plaque hemorrhage, fissuring, ischemia and myocardial infarction are commonly observed. Development of advanced coronary artery disease with ischemia and myocardial infarction has previously only been reported in animal models employing the combination of vascular injury and cholesterol-enriched diet. Thus the FHC swine represent a unique model for the study of coronary artery disease. If efforts to down-size these swine are successful, they could also provide a valuable model in which to study restenosis. They also show promise as a model for testing hypolipidemics. Treatment with fenofibrate (45 mg/kg) for 3 weeks resulted in significant reductions in total cholesterol (26%), LDL (25%), apo B (24%) and triglycerides (36%). The hyperlipidemit and diabetic hamster, a novel animal model Simionescu M, Popov D, w, Hasu M, Costache G, Faiter S, Vulpanovici A, Stancu C, Simionescu N, Inst. of Cellular Biol. and Pathol., 8 B.P. Hasdeu Str., Bucharest-79691,
Romania
The purpose of these studies was to develop an animal model for investigating the pathobiochemical events that underline diabetes complicated with accelerated atherosclerosis. 180 Golden Syrian male hamsters were brought to three experimental conditions: streptozotocin-induced diabetes, diet-induced hyperlipidemia, and a combination of the above two perturbations, concomitantly or successively induced. At time intervals ranging from 2 to 26 weeks, the animals were examined for changes in some plasma constituents and ultrastmctural modifications of relevant tissues. Regardless of the timing of their combination, experimental diabetes and atherosclerosis were manifested by pronounced plasma alterations e.g. increase in cholesterol, apolipoprotein B and peroxides, glycation of LDL and of albumin, and the appearance of irreversibly glycated albumin. These coexisted with micro- and macroangiopathic lesions characteristic of each of these abnormalities, i.e. capillary narrowing and thickening of their basal laminae, proliferation of extracellular matrix (retina, glomeruli, myocardium), intimal accumulation of modified lipoproteins and
macrophage-derived foam cells in the aorta, coronaries and cardiac valves, leading to formation of atherosclerotic plaques. With time, the latter develop cholesterol crystals and a necrotic core. Remarkably, in diabetes alone, although the level of plasma cholesterol was not significantly affected, there was an increase in plasma peroxides and in triglyceride-rich VLDL associated with the development of atherosclerotic plaques, predominantly of fibrolipid type. This demonstrates that diabetic alterations of the arterial walls predisposes to accelerated atherogenesis in a sequence of cellular and biochemical events easily identifiable in the diabetic-athero hamster model. Lessons derived for haman atherosclerosis from the study of the WIUIL rabbit. Tanaka M, Otani H, Yokode M, Dept. of Geriatric Med., m, Faculty of Med., Kyoro University, 54 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto 606-01. Japan
The Watanabe heritable hyperlipidemic (WI-U-IL) rabbit has a genetic defect that is identical to that of familial hypercholesterolemia (FH) in humans. In the homozygous form, this defect leads to a nearly complete deficiency of LDL receptors. As a result, the plasma level in these rabbits is elevated lO-20-fold above normal. LDL deposits and is oxidatively modified in the arterial wall, producing xanthoma and atheromas, as in FH patients. Therefore, we can use WHHL rabbits as animal models for studying human FH. So far we demonstrated that the decreased hepatic LDL receptors elevate LDL particles by overproduction and undercatabolism of LDL particles in blood. In this study, we asked whether the production and secretion of apo B-containing lipoprotein is different between normal and WHHL rabbits, and found that it is not. The content of cholesteryl ester in the hepatocytes regulates the degradation of apo B protein itself. Even if LDL receptors are not available in WHHL rabbit hepatocytes, LDL cholesterol accumulates via a non-LDL receptor pathway. Therefore, as long as the hepatic content of cholesteryl ester in WHHL rabbits is the same as that of normal rabbits, production and secretion of apo B- containing lipoproteins is similarly regulated. A new rabbit model of atherosclerosis wJH, Fennessy PA, MandersonJA, Campbell GR, Centre for Research in Vascular Biology, Dept. of Anatomical Sciences, Univ. of Queensland, Brisbane, QLD 4072 Australia
In humans, atherosclerosis develops in those arteries which have pre-existing myointimal thickenings either diffusely along the vessel or as ‘intimal cushions’ at branch points. These thickenings begin to develop shortly after birth, and by the second decade of life diffuse intimal thickenings can be up to five times the thickness of the media in vessels such as the left descending coronary artery. Atherosclerosis rarely develops in vessels where the endothelium lies directly on the internal elastic lamina. Therefore, in order to model as closely as possible the human disease, the right carotid artery of the rabbit was de-endothelialized with a 2F Fogarty balloon catheter. This resulted in smooth muscle cells from the inner part of the media undergoing phenotypic change characterized by a decrease in the volume fraction of myofilaments (Vvmyo) from 67.9 + 3.6% to 42.7 f 3.38, followed by migration through fenestrations in the internal elastic lamina, and proliferation. During the development phase of the thickening (the first 2 weeks) the Vvmyo of the smooth muscle cells was low (38.8 + 1.0%). However, after 6 weeks this started to increase
Atherosclerosis X, Montreal, October 1994