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Apolipoprotein AI Transgene Corrects Apolipoprotein E Deficiency-Induced Atherosclerosis in Mice

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Apolipoprotein AI Transgene Corrects Apolipoprotein E Deficiency-Induced Atherosclerosis in Mice Apolipoprotein AI transgene corrects apolipoprotein E deficiency-induced atherosclerosis in mice. C Pászty, … , J Verstuyft, E M Rubin J Clin Invest. 1994;94(2):899-903. https://doi.org/10.1172/JCI117412. Research Article Apolipoprotein E (apo E)-deficient mice are severely hypercholesterolemic and develop advanced atheromas independent of diet. The C57BL/6 strain differs from most inbred strains by having lower HDL concentrations and a high risk of developing early atherosclerotic lesions when fed an atherogenic diet. The relative HDL deficiency and atherosclerosis susceptibility of the C57BL/6 strain are corrected with the expression of a human apolipoprotein AI (apo AI) transgene in this genetic background. To examine if increases in apo AI and HDL are also effective in minimizing apo E deficiency-- induced atherosclerosis, we introduced the human apo AI transgene into the hypercholesterolemic apo E knockout background. Similar elevations of total plasma cholesterol occurred in both the apo E knockout and apo E knockout mice also expressing the human apo AI transgene. The latter animals, however, also showed a two- to threefold increase in HDL and a sixfold decrease in susceptibility to atherosclerosis. This study demonstrates that elevating the concentration of apo AI reduces atherosclerosis in apo E deficient-mice and suggests that elevation of apo AI and HDL may prove to be a useful approach for treating unrelated causes of heightened atherosclerosis susceptibility. Find the latest version: https://jci.me/117412/pdf Rapid Publication Apolipoprotein Al Transgene Corrects Apolipoprotein E Deficiency-induced Atherosclerosis in Mice Chris Paszty,* Nobuyo Maeda,* Judy Verstuyft,* and Edward M. Rubin* *Life Sciences Division, Lawrence Berkeley Laboratory, University of California, Berkeley, California 94720; and tDepartment of Pathology, University of North Carolina, Chapel Hill, North Carolina 27599 Abstract inbred strains of mice (10), as defined by the development of aortic lipid deposits after a dietary insult, results from the inter- Apolipoprotein E (apo E)-deficient mice are severely hyper- action of multiple genes. Several murine atherosclerosis suscep- cholesterolemic and develop advanced atheromas indepen- tibility loci have been mapped (11-13), although no specific dent of diet. The C57BL/6 strain differs from most inbred genes or gene products have yet been identified. strains by having lower HDL concentrations and a high The C57BU6 inbred strain of mice is susceptible to diet- risk of developing early atherosclerotic lesions when fed an induced atherosclerosis and, unlike resistant inbred strains of atherogenic diet. The relative HDL deficiency and athero- mice, has a significantly lower HDL concentration when fed an sclerosis susceptibility of the C57BL/6 strain are corrected atherogenic diet. In addition, males and females of this strain with the expression of a human apolipoprotein Al (apo Al) respond differently to an atherogenic diet: females are more transgene in this genetic background. To examine if in- susceptible to atherosclerosis and have lower HDL levels than creases in apo Al and HDL are also effective in minimizing males (14). It was these two observations that implicated low apo E deficiency-induced atherosclerosis, we introduced the HDL as a possible cause of the increased susceptibility to ath- human apo AI transgene into the hypercholesterolemic apo erosclerosis found in the C57BUJ6 strain. Recent studies in E knockout background. Similar elevations of total plasma genetically engineered C57BL/6 mice have examined whether cholesterol occurred in both the apo E knockout and apo E increasing the concentration of HDL in these mice could render knockout mice also expressing the human apo Al transgene. them resistant to diet-induced atherosclerosis. In these studies, The latter animals, however, also showed a two- to threefold the (human) apo AI gene, a major determinant of HDL concen- increase in HDL and a sixfold decrease in susceptibility to tration, was introduced and expressed in this inbred strain (15). atherosclerosis. This study demonstrates that elevating the The increase in HDL levels in the apo Al transgenic mice was concentration of apo Al reduces atherosclerosis in apo E accompanied by a dramatic reduction in susceptibility to diet- deficient-mice and suggests that elevation of apo Al and induced atherosclerosis (5, 7). HDL may prove to be a useful approach for treating unre- apo E knockout (apo E KO)' mice, derived from embryonic lated causes of heightened atherosclerosis susceptibility. (J. stem cells in which the murine apo E gene had been inactivated Clin. Invest. 1994. 94:899-903.) Key words: atherogenesis- via gene targeting, has provided a new murine model for study- transgenic mice * high density lipoproteins * lipoproteins ing atherosclerosis susceptibility (16, 17) that does not require a dietary insult. These animals lack apo E, a critical ligand in Introduction receptor-mediated removal of nearly all classes of lipoproteins, and have massive hypercholesterolemia, even when fed a low Cardiovascular disease remains the chief cause of death in af- fat, low cholesterol diet. The development of atherosclerosis in fluent nations (1), and atherosclerosis accounts for the majority these animals is significantly more severe and rapidly progres- of these deaths. The common forms of atherosclerotic heart sive than that of C57BIJ6 mice. Furthermore, the atheroscle- disease are the result of the interactions of multiple genetic and rotic lesions in apo E KO mice are found throughout the ani- environmental factors (2). The mouse has been used increas- mal's arterial tree, while in C57BU6 mice they are localized ingly as a model system to study the genetics of atherosclerosis primarily to the proximal aorta. (3-9) because of the availability of both classical and modern This study examines the impact of elevated HDL levels (due genetic approaches for studying this complex disorder in a man- to high levels of human apo Al) on the severe atherosclerosis ner not possible in humans. Atherosclerosis susceptibility in susceptibility in hypercholesterolemic (due to the absence of plasma apo E) mice. In these studies, the human apo Al transgene was bred into the apo E KO background, which re- sulted in mice hemizygous for the human apo AI transgene as Address correspondence to Edward M. Rubin, Life Sciences Division, well as homozygous for the inactivated murine apo E allele Lawrence Berkeley Laboratory, University of California, Berkeley, CA (apo Al/apo E KO mice). The apo E KO and apo AI/apo E KO 94720. animals were compared with regard to lipoprotein parameters Received for publication 18 January 1994 and in revised form 11 April 1994. and atherosclerosis susceptibility. J. Clin. Invest. C) The American Society for Clinical Investigation, Inc. 0021-9738/94/08/0899/05 $2.00 1. Abbreviations used in this paper: IDL, intermediate density lipopro- Volume 94, August 1994, 899-903 tein; KO, knockout. Apolipoprotein AI, Transgenic Apolipoprotein E Knockout, Atherosclerosis 899 Table I. Atherosclerosis, Lipoproteins, and Apolipoproteins Apolipoproteins* Cholesterol* Atherosclerosis* Murine Murine Human Total Non- HDLJ Mean lesion area/ Genotype (n) Sex apo E apo Al apo AI apo Al HDL HDL Total total section (mm2) AI/E KO (27) M + F 0 8 (1)11 82 (8)11 90 (9)11 101 (3)11 465 566 (22) 0.18 776 (233)1 E KO (34) M + F 0 55 (3) 0 55 (3) 31 (2) 447 478 (22) 0.07 5002 (924) AIVE KO (10) F 0 10 (1)11 68 (8)11 78 (9)ll 102 (4)11 452 554 (50) 0.18 1015 (484)11 E KO (21) F 0 52 (2) 0 52 (2) 28 (2) 419 447 (23) 0.06 6612 (1317) AI/E KO (17) M 0 6 (0.5)l' 93 (13)11 100 (13)1 100 (4)11 474 574 (20) 0.18 611 (218)11 E KO (13) M 0 60 (5) 0 60 (5) 36 (4) 491 527 (40) 0.07 2498 (517) C57BLU6 (11) F T/C 107 (2) 0 107 (2) 49 20 69 0.70 0 * The values shown represent the mean (± SEM) in milligrams per deciliter for the number of animals (n). * The values shown represent the mean (± SEM) for the data set presented in Fig. 2. 1 The values shown represent the mean total cholesterol minus the mean non-HDL cholesterol in milligrams per deciliter. 11 Indicates significant differences (P < 0.005) between AVE KO versus E KO genotype groups. tIndicates significant differences (P < 0.05) between AYE KO versus E KO genotype groups. Methods 25% gelatin. For the quantitative analysis, the mean lesion area per section per animal was determined as described previously (15). We Animals. The human apo Al transgenic mice created in the C57BL/6 quantitated four 10-,um aortic sections each separated by 80 Am. The background have been described previously (15). The apo E KO mice first and most proximal section to the heart was taken 80 um distal to originally made in the 129/Ola background (18) were backcrossed to the point where the aorta first becomes rounded. The area of oil red 0 C57BLU6 for three generations. Mice homozygous for the human apo staining fatty streak lesions in each section was determined using a Al transgene were bred with apo E KO (87% C57BLJ6, 13% 129/Gla) calibrated eyepiece, and the mean lesion area per section per animal mice to produce offspring both hemizygous for apo Al and heterozygous was calculated for each group of animals. The coded slides were exam- for the apo E null allele. These were backcrossed to apo E KO mice to ined blind in two separate analyses by the same examiner and gave produce the apo AI/apo E KO and apo E KO littermates used in this consistent results (r > 0.92). study. Total cholesterol levels as well as the presence or absence of Statistical analysis. The significance of differences (P values) be- mouse apo E were used to distinguish apo E null allele heterozygotes tween means was tested by using the Mann-Whitney U test for nonpara- from homozygotes (16-18).
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