CN 4321262/ R 371 [ ] 100723949 (2003) 1120420371205 1 1 ( 710061 ; 1. ) [ ] ; ; ; [ ] (a) AI B E2-152 12 B mrna 1 (a) A - WHHL [ ] Q23 R363 [ ] A 1 1. 1 (Oryctolagus cuniculus) (Lagomorphs) [1 ] 0. 2 % 2. 1. 0 % HDL LDL LDL CEPT B B48 VLDL A 2 2 (low density lipoprotein LDL) [3 B48 ] ; (cholesteryl ester transfer protein CETP) [4 CETP As ] ; ( ) As CEPT [5 ] As ( 1) 1. 2 (atherosclerosis As) As As [1 ] As 2 1 3 6 (fibrous 70 % plaques) As (collagen fibers) LDL (necrotic core) (cholesterol crystals) [6 ] LDL ( high [2 density lipoprotein HDL) ] ; [7 ] B48 mrna B100 1. 3 B100 (Watanabe heritable hyperlipidemic WHHL) B48 B48 VLDL (St. Thomas s hospital strain STHS) As [ ] 2003205212 [ ] 2003207209 [1 ] WHHL [ ] 1965 ( Yoshio Watanabe) 1980 (Japanese white) (hyperlipi2
372 ISSN 100723949 Chin J Arterioscler Vol 11 No 4 demia) [8 ] WHHL LDL 2. As As WHHL 8 14 WHHL VLDL IDL LPL [9 (familial hypercholesterolemia FH) ] LDL HDL HDL LDL As WHHL LDL APOBEC LDL (a) (a) As As A HDL As La Ville B100 HDL LDL (New Zealand white NZW) VLDL IDL [10 ] E2 As HDL ( ) (very low density lipoprotein VLDL) VLDL IDL E3 HDL LDL (intermediate density lipopro2 152 tein IDL) VLDL LDL cdna 3 Duverger [15 ] A 11 kb DNA( ) 1. 4 A 80 1 000 mgπl 0. 4 % 14 A ( ) Hammer [11 ] 1985 mgπl P < 0. 001) (metallothionein) (15 % 12 % 30 % 18 % P < 0. 01) 1993 Hoeg [12 ] 46 % (116 31 247 39 molπg P < Perevozchikov [13 ] AI 0. 01) (overexpression) A [16 A 1994 As ] Mackness [17 ] [14 ] Duverger AI 14 As (26 % 15 % 29 % 16 % P > 0. As 05) (a) AI 2. 2 B B E2 E3- [18 ] 80 kb B DNA (lecithin2cholesterol acyltransferase ) NZW (lipoprotein lipase LPL) 152 (152lipoxygenase 152LO) B100 12 (matrix metalloproteinase212 MMP212) B100 B48 B mrna 1 (apoli2 [3 B mrna ] poprotein B mrna2editing enzyme catalytic polypeptide 1 APOBEC2 B100 120 940 mgπl 1) (a) A LPL LDL 2 3 HDL WHHL As 2 B100 LDL (fraction) LDL As LDL As (24 nm 27. 5 nm) As B100 As [18 ] 2 2. 1 A VLDL IDL HDL As As As As NZW AI HDL 2 (680 110 370 30 2. 3 (a) (a) (a) (a) 1993 Perevozchikov [13 ] AI
CN 4321262/ R 373 [26 (a) ] APOBEC21 (a) B (a) APOBEC21 [19 (particles) ] Rouy LDL [20 ] (a) B mrna APOBEC21 (a) YAC 25 mgπ B100 LDL VLDL IDL L cdna 18 45 mgπl LDL HDL [26 (a) ] (a) (a) [19 ] [21 (a) As ] [27 ] As (a) 2. 7 [14 As 0. 3 % 16 ] EΠCI cdna 6 (a) 1 (a) [28 ] 10 RNA [22 As ] 2. 4 E2 E2 (Cys112 Cys158) 58 % 0. 3 3 Huang [23 ] 5 (type hyperlipoproteinemia) E2 1Π3 As Huang E2 E2 300 700 mgπl 40 mgπl 2. 8 HDL LPL As HDL Araki [29 ] 2 ( 2actin) LPL cd2 2 NA LPL VLDL VLDL IDL Northern LPL 11 LPL 4 (post heparin plasma) LPL 650 gπl E2 As 80 % HDL 59 % LPL VLDL 2. 5 E3 [24 ] E3 DNA LPL [30 As ] E3 (Cys112 Arg158) 3 2. 9 - E3 60 110 130 mgπl - () VLDL LDL 1996 Hoeg [31 ] VLDL ( > 36 nm) DNA NZW 20 % E VLDL Huang [25 ] Northern E3 VLDL VLDL VLDL E HDL 0. 3 % 17 2. 6 B mrna 1 LDL APOBEC21 HDL VLDL IDL 42 % IDL LDL HDL 20 % 5 % 35 %
374 ISSN 100723949 Chin J Arterioscler Vol 11 No 4 [31 As ] Mehlum [32 ] [14 28 VLDL LDL VLDL ] ; E 14 27 HDL 2 VLDL LDL [24 ] As 2. 10 152 152 (152LO) As B (a) As LDL Shen [33 ] 152LO (a) (a) As 152LO 10 % 0. 25 % 13. 5 VLDL HDL 3 (9. 8 % 6. 6 % 17. 8 % 15. 0 % P < 0. 05) 152LO ( 3) WHHL 152LO WHHL As [31 As ] 26 % (7. 7 % 5. 7 % 20. 7 % 19. 4 % P < 0. 05) As 152LO 3. [34 ] Cyrus [35 ] 152LO As 152LO As 2. 11 12 12 (MMP212) As MMP212 As As Wang [36 ] LPL MMP212 ( ) MMP212 mrna MMP212 As As MMP212 As 2. 12 WHHL As 1993 Hoeg [12 ] AI WHHL HDL ES (knock out) (240 20 mgπl 60 10 mgπl) AI WHHL As As [37 ] Brousseau [38 ] WHHL LDL LDL As [ ] [39 (a) As ] (a) WHHL (a) As As (calcification) (a) As [40 ] 2. 13 Barbagallo [41 ] E E 10 E 85 % VLDL + IDL + LDL 87 % E Rouy [42 ] (a) B B [32 ] As As Mehlum1997 Hoeg 1996 HL As As Amar 2000 Taylor 1997 (a) B B Chiesa 1992 Fan 1999 E3 As As ( ) Shimano 1992 Fan 1998 152LO As As Cycus 1999 Shen 1996 Levak2Frank 1995 Koike 2002 [1 ] Manning PJ Ringler DH Newcomer CE. The biology of the laboratory rabbits. Academic Press Inc San Diego USA 1994 ; 2942230 [2 ] Fan J Challah M Watanabe T. Transgenic rabbit models for biomedical re2 search: current status basic methods and future perspectives. Pathol Int 1999 49 : 5832594 [3 ] Greeve J Altkemper I Dieterich J H et al. Apolipoprotein B mrna editing in 12 different mammalian species : hepatic expression is reflected in low concentra2 tions of apo B2containing lipoproteins. J Lipid Res 1993 34 : 1 3672383 [4 ] Nagashima M McLean JW Lawn RL. Cloning and mrna tissue distribution of rabbit cholesteryl ester transfer protein. J Lipid Res 1988 29 : 1 6432649 [5 ] Fan J Watanabe T. Cholesterol2fed and transgenic rabbit models for the study of atherosclerosis. J Atheroscler Thromb 2000 7 : 26232 [6 ] Daley SJ Herderick EE Cornhill JF et al. Cholesterol2fed and casein2fed rabbit models of atherosclerosis. Part 1 : Differing lesion area and volume despite equal plasma cholesterol levels. Arterioscler Thromb 1994 14 : 952104
CN 4321262/ R 375 [7 ] Ross R. The pathogenesis of atherosclerosis : A perspective for the 1990s. Nature 1993 362 : 8012809 [8 ] Watanabe Y. Serial inbreeding of rabbits with hereditary hyperlipidemia (WHHL2rabbit). Atherosclerosis 1980 36 : 2612268 [9 ] Kita T Brown MS Watanabe Y et al. Deficiency of low density lipoprotein receptors in liver and adrenal gland of the WHHL rabbit an animal model of fa2 milial hypercholesterolemia. Proc Natl Acad Sci USA 1981 78 : 2 2682272 [10 ] La Ville A Turner PR Pittilo RM et al. Hereditary hyperlipidemia in the rabbit due to overproduction of lipoproteins. Arteriosclerosis 1987 7 : 1052124 [11 ] Hammer RE Pursel VG Rexroad CE et al. Production of transgenic rabbits sheep and pigs by microinjection. Nature 1985 315 : 6802683 [12 ] Hoeg JM Vaisman BL Demosky SJ et al. Development of transgenic Watan2 abe Heritable Hyperlipidemic rabbits expressing human apolipoprotein A2I. Circulation 1993 88 : I22 [13 ] Perevozchikov AP Vaisman BL Sorokin AV et al. Study of the effect of the cdna for the human A2I gene in transgenic rabbits : modeling the neurological syndrome of human Tangier disease. Molekuliarnaia Biologi 1993 27 : 24237 [14 ] Fan J Wang J Bensadoun A et al. Overexpression of hepatic lipase in transgenic rabbits leads to a marked reduction of plasma high density lipoproteins and intermediate density lipoproteins. Proc Natl Acad Sci USA 1994 91 : 8 7242728 [15 ] Duverger N Viglietta C Berthou L et al. Transgenic Rabbits Expressing Hu2 man Apolipoprotein A2I in the Liver. Arterioscler Thromb Vasc Biol 1996 16 : 1 4242429 [16 ] Duverger N Kruth H Emmanuel F et al. Inhibition of Atherosclerosis De2 velopment in Cholesterol2Fed Human Apolipoprotein A2I2Transgenic Rabbits. Circulation 1996 94 : 7132717 [17 ] Mackness M Boullier A Hennuyer N et al. Paraoxonase activity is reduced by a pro2atherosclerotic diet in rabbits. Biochem Biophys Res Commun 2000 269 : 2322236 [18 ] Fan J McCormick SPA Krauss RM et al. Overexpression of human apoli2 poprotein B100 in transgenic rabbits results in increased levels of LDL and de2 creased levels of HDL. Arterioscler Thromb Vasc Biol 1995 15 : 1 8892899 [19 ] Fan J Araki M Wu L et al. Assembly of lipoprotein (a) in transgenic rab2 bits expressing human apolipoprotein ( a). Biochem Biophys Res Commun 1999 255 : 6392644 [20 ] Rouy D Duverger N Lin SD et al. Apolipoprotein (a) yeast artificial chro2 mosome transgenic rabbits. J Biol Chem 1998 273 : 1 2472251 [21 ] Fan J Shimoyamada H Sun H et al. Transgenic rabbits expressing human apolipoprotein (a) develop more extensive atherosclerotic lesions in response to a cholesterol2rich diet. Arterioscler Thromb Vasc Biol 2001 21 : 88294 [22 ] Ichikawa T Unoki H Sun H et al. Lipoprotein (a) promotes smooth muscle cell proliferation and dedifferentiation in atherosclerotic lesions of human apo (a) transgenic rabbits. Am J Pathol 2002 160 : 2272236 [23 ] Huang Y Schwendner SW Rall SC et al. Apolipoprotein E2 transgenic rab2 bits: modulation of the type III hyperlipoproteinemic phenotype by estrogen and occurrence of spontaneous atherosclerosis. J Biol Chem 1997 272 : 22 6852 694 [24 ] Fan J Zhong2Sheng J Huang Y et al. Increased expression of apolipoprotein E in transgenic rabbits results in reduced levels of very low density lipoproteins and an accumulation of low density lipoproteins in plasma. J Clin Invest 1998 101 : 2 1512164 [25 ] Huang Y Ji ZS Brecht WJ et al. Overexpression of apolipoprotein E3 in transgenic rabbits causes combined hyperlipidemia by stimulating hepatic VLDL production and impairing VLDL lipolysis. Arterioscler Thromb Vasc Biol 1999 19 : 2 9522959 [26 ] Yamanaka S Balestra ME Ferrell LD et al. Apolipoprotein B mrna2editing protein induces hepatocellular carcinoma and dysplasia in transgenic animals. Proc Natl Acad Sci USA 1995 92 : 8 4832487 [27 ] Qian X Balestra ME Yamanaka S et al. Low expression of the apolipopro2 tein B mrna2editing transgene in mice reduces LDL levels but does not cause liver dysplasia or tumors. Arterioscler Thromb Vasc Biol 1998 18 : 1 0132020 [28 ] Fan J Wang J Ji ZS et al. Transgenic rabbits overexpression human hepatic lipase have reduced level of high density lipoproteins and intermediate density li2 poproteins and diminished response to dietary cholesterol. Circulation 1994 90 (Suppl I) : 298 [29 ] Araki M Fan J Challah M et al. Transgenic rabbits expressing human li2 poprotein lipase. Cytotechnology 2000 33 : 93299 [30 ] Fan J Unoki H Kojima N et al. Overexpression of lipoprotein lipase in transgenic rabbits inhibits diet2induced hypercholesterolemia and atherosclerosis. J Biol Chem 2001 276 : 40 0712079 [31 ] Hoeg JM Santamarina2Fojo S B rard AM et al. Overexpression of lecithin : cholesterol acyltransferase in transgenic rabbits prevents diet2induced atheroscle2 rosis. Proc Natl Acad Sci USA 1996 93 : 11 4482453 [32 ] Mehlum A Gjernes E Solberg LA et al. Overexpression of human lecithin : cholesterol acyltransferase in mice offers no protection against diet2induced ather2 osclerosis. APMIS 2000 108 : 3362342 [33 ] Shen J Kuhn H Petho2Schramm A et al. Transgenic rabbits with the inte2 grated human 152lipoxygenase gene driven by a lysozyme promoter : macrophage2 specific expression and variable positional specificity of the transgenic enzyme. FASEB J 1995 9 : 1 6232631 [34 ] Shen J Herderick E Cornhill JF et al. Macrophage2mediated 152lipoxygen2 ase expression protects against atherosclerosis development. J Clin Invest 1996 98 : 2 2012208 [35 ] Cyrus T Pratico D Zhao L et al. Absence of 12Π152lipoxygenase expression decreases lipid peroxidation and atherogenesis in apolipoprotein e2deficient mice. Circulation 2001 103 : 2 2772282 [36 ] Wang X Unoki H Liang J et al. Transgenic rabbits with specific expression of human matrix metalloproteinase212 in macrophage. Lab Invest 2003 (in press) [37 ] Emmanuel F Caillaud JM Hennuyer N et al. Overexpression of human apo2 lipoprotein A2I inhibits atherosclerosis development in Watanabe rabbits. Cir2 culation 1996 94 : I2632 [38 ] Brousseau ME Kauffman RD Herderick EE et al. modulates athero2 genic plasma lipoproteins and the extent of atherosclerosis only in the presence of normal LDL receptors in transgenic rabbits. Arterioscler Thromb Vasc Biol 2000 20 : 4502458 [39 ] Fan J Sun H Unoki H et al. Enhanced atherosclerosis in Lp (a) WHHL transgenic rabbits. Ann NY Acad Sci 2001 947 : 3622365 [40 ] Sun H Unoki H Wang X et al. Lipoprotein (a) enhances advanced athero2 sclerosis and vascular calcification in WHHL transgenic rabbits expressing human apolipoprotein (a). J Biol Chem 2002 277 : 47 4862492 [41 ] Barbagallo CM Fan J Blanche PJ et al. Overexpression of human hepatic lipase and Apo E in transgenic rabbits attenuates response to dietary cholesterol and alters lipoprotein subclass distributions. Arterioscler Thromb Vasc Biol 1999 19 : 6252632 [42 ] Rouy D Duverger N Lin SD et al. Apolipoprotein (a) yeast artificial chro2 mosome transgenic rabbits. Lipoprotein ( a) apolipoprotein B. J Biol Chem 1998 273 : 1 2472251 () assembly with human and rabbit