(a) AI B E2-152 B48 CEPT [5 ] As ( 1) 1. 2 (atherosclerosis,as), As 0 %, (necrotic core),

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1 CN / R 371 [ ] (2003) ( ; 1. ) [ ] ; ; ; [ ] (a) AI B E B mrna 1 (a) A - WHHL [ ] Q23 R363 [ ] A (Oryctolagus cuniculus) (Lagomorphs) [1 ] 0. 2 % % 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 (fibrous 70 % plaques) As (collagen fibers) LDL (necrotic core) (cholesterol crystals) [6 ] LDL ( high [2 density lipoprotein HDL) ] ; [7 ] B48 mrna B B100 (Watanabe heritable hyperlipidemic WHHL) B48 B48 VLDL (St. Thomas s hospital strain STHS) As [ ] [ ] [1 ] WHHL [ ] 1965 ( Yoshio Watanabe) 1980 (Japanese white) (hyperlipi2

2 372 ISSN 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 mgπl 0. 4 % 14 A ( ) Hammer [11 ] 1985 mgπl P < ) (metallothionein) (15 % 12 % 30 % 18 % P < 0. 01) 1993 Hoeg [12 ] 46 % ( 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) B (matrix metalloproteinase212 MMP212) B100 B48 B mrna 1 (apoli2 [3 B mrna ] poprotein B mrna2editing enzyme catalytic polypeptide 1 APOBEC2 B mgπl 1) (a) A LPL LDL 2 3 HDL WHHL As 2 B100 LDL (fraction) LDL As LDL As (24 nm nm) As B100 As [18 ] A VLDL IDL HDL As As As As NZW AI HDL 2 ( (a) (a) (a) (a) 1993 Perevozchikov [13 ] AI

3 CN / 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 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 % Huang [23 ] 5 (type hyperlipoproteinemia) E2 1Π3 As Huang E2 E 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) E 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 % B mrna 1 LDL APOBEC21 HDL VLDL IDL 42 % IDL LDL HDL 20 % 5 % 35 %

4 374 ISSN Chin J Arterioscler Vol 11 No 4 [31 As ] Mehlum [32 ] [14 28 VLDL LDL VLDL ] ; E HDL 2 VLDL LDL [24 ] As (152LO) As B (a) As LDL Shen [33 ] 152LO (a) (a) As 152LO 10 % % VLDL HDL 3 (9. 8 % 6. 6 % % % P < 0. 05) 152LO ( 3) WHHL 152LO WHHL As [31 As ] 26 % (7. 7 % 5. 7 % % % P < 0. 05) As 152LO 3. [34 ] Cyrus [35 ] 152LO As 152LO As (MMP212) As MMP212 As As Wang [36 ] LPL MMP212 ( ) MMP212 mrna MMP212 As As MMP212 As WHHL As 1993 Hoeg [12 ] AI WHHL HDL ES (knock out) ( mgπl mgπl) AI WHHL As As [37 ] Brousseau [38 ] WHHL LDL LDL As [ ] [39 (a) As ] (a) WHHL (a) As As (calcification) (a) As [40 ] 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 LO 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 ; [2 ] Fan J Challah M Watanabe T. Transgenic rabbit models for biomedical re2 search: current status basic methods and future perspectives. Pathol Int : [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 : [4 ] Nagashima M McLean JW Lawn RL. Cloning and mrna tissue distribution of rabbit cholesteryl ester transfer protein. J Lipid Res : [5 ] Fan J Watanabe T. Cholesterol2fed and transgenic rabbit models for the study of atherosclerosis. J Atheroscler Thromb : [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 :

5 CN / R 375 [7 ] Ross R. The pathogenesis of atherosclerosis : A perspective for the 1990s. Nature : [8 ] Watanabe Y. Serial inbreeding of rabbits with hereditary hyperlipidemia (WHHL2rabbit). Atherosclerosis : [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 : [10 ] La Ville A Turner PR Pittilo RM et al. Hereditary hyperlipidemia in the rabbit due to overproduction of lipoproteins. Arteriosclerosis : [11 ] Hammer RE Pursel VG Rexroad CE et al. Production of transgenic rabbits sheep and pigs by microinjection. Nature : [12 ] Hoeg JM Vaisman BL Demosky SJ et al. Development of transgenic Watan2 abe Heritable Hyperlipidemic rabbits expressing human apolipoprotein A2I. Circulation : 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 : [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 : [15 ] Duverger N Viglietta C Berthou L et al. Transgenic Rabbits Expressing Hu2 man Apolipoprotein A2I in the Liver. Arterioscler Thromb Vasc Biol : [16 ] Duverger N Kruth H Emmanuel F et al. Inhibition of Atherosclerosis De2 velopment in Cholesterol2Fed Human Apolipoprotein A2I2Transgenic Rabbits. Circulation : [17 ] Mackness M Boullier A Hennuyer N et al. Paraoxonase activity is reduced by a pro2atherosclerotic diet in rabbits. Biochem Biophys Res Commun : [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 : [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 : [20 ] Rouy D Duverger N Lin SD et al. Apolipoprotein (a) yeast artificial chro2 mosome transgenic rabbits. J Biol Chem : [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 : [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 : [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 : [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 : [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 : [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 : [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 : [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 (Suppl I) : 298 [29 ] Araki M Fan J Challah M et al. Transgenic rabbits expressing human li2 poprotein lipase. Cytotechnology : [30 ] Fan J Unoki H Kojima N et al. Overexpression of lipoprotein lipase in transgenic rabbits inhibits diet2induced hypercholesterolemia and atherosclerosis. J Biol Chem : [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 : [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 : [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 : [34 ] Shen J Herderick E Cornhill JF et al. Macrophage2mediated 152lipoxygen2 ase expression protects against atherosclerosis development. J Clin Invest : [35 ] Cyrus T Pratico D Zhao L et al. Absence of 12Π152lipoxygenase expression decreases lipid peroxidation and atherogenesis in apolipoprotein e2deficient mice. Circulation : [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 : 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 : [39 ] Fan J Sun H Unoki H et al. Enhanced atherosclerosis in Lp (a) WHHL transgenic rabbits. Ann NY Acad Sci : [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 : [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 : [42 ] Rouy D Duverger N Lin SD et al. Apolipoprotein (a) yeast artificial chro2 mosome transgenic rabbits. Lipoprotein ( a) apolipoprotein B. J Biol Chem : () assembly with human and rabbit