Atherosclerosis in the apolipoprotein-E-deficient mouse: a decade of progress.

Arguably the most critical advancement in the elucidation of factors affecting atherogenesis has been the development of mouse models of atherosclerosis. Among available models, the apolipoprotein E-deficient (apoE-/-) mouse is particularly popular because of its propensity to spontaneously develop atherosclerotic lesions on a standard chow diet. A Medline search reveals over 645 articles dedicated to studies using this reliable and convenient "super" animal model since its inception (Piedrahita JA et al, Proc Natl Acad Sci U S A 1992;89:4471-4475; Plump AS et al, Cell 1992;71:343-353) with a more or less steady increase from year to year. This review will examine our present understanding of the pathology and progression of plaques in this animal and highlight some of the nutritional, pharmacological, and genetic studies that have enhanced this understanding.

[1]  Lan Li,et al.  C-Reactive Protein Accelerates the Progression of Atherosclerosis in Apolipoprotein E–Deficient Mice , 2004, Circulation.

[2]  M. Linton,et al.  Inactivation of Macrophage Scavenger Receptor Class B Type I Promotes Atherosclerotic Lesion Development in Apolipoprotein E–Deficient Mice , 2003, Circulation.

[3]  J. Phillips,et al.  Rosiglitazone Reduces the Accelerated Neointima Formation After Arterial Injury in a Mouse Injury Model of Type 2 Diabetes , 2003, Circulation.

[4]  B. Bennett,et al.  Chronic inhibition of cyclooxygenase-2 does not alter plaque composition in a mouse model of advanced unstable atherosclerosis. , 2003, Cardiovascular research.

[5]  A. Rigotti,et al.  Influence of the HDL Receptor SR-BI on Lipoprotein Metabolism and Atherosclerosis , 2003, Arteriosclerosis, thrombosis, and vascular biology.

[6]  R. F. Hoyt,et al.  Hepatic lipase expression in macrophages contributes to atherosclerosis in apoE-deficient and LCAT-transgenic mice. , 2003, The Journal of clinical investigation.

[7]  M. Hayden,et al.  Efflux and Atherosclerosis: The Clinical and Biochemical Impact of Variations in the ABCA1 Gene , 2003, Arteriosclerosis, thrombosis, and vascular biology.

[8]  S. Akira,et al.  Reduced atherosclerosis in interleukin-18 deficient apolipoprotein E-knockout mice. , 2003, Cardiovascular research.

[9]  J. Alvarez‐Leite,et al.  Monocyte chemoattractant protein-1 involvement in the α-tocopherol-induced reduction of atherosclerotic lesions in apolipoprotein E knockout mice , 2003, British Journal of Nutrition.

[10]  T. Gjøen,et al.  Hepatic scavenger receptor class B, type I is stimulated by peroxisome proliferator-activated receptor γ and hepatocyte nuclear factor 4α , 2003 .

[11]  M. Burnett,et al.  Effects of MF-tricyclic, a selective cyclooxygenase-2 inhibitor, on atherosclerosis progression and susceptibility to cytomegalovirus replication in apolipoprotein-E knockout mice. , 2003, Journal of the American College of Cardiology.

[12]  Minghan Wang,et al.  Modulation of PPARγ activity with pharmaceutical agents: Treatment of insulin resistance and atherosclerosis , 2003, Journal of cellular biochemistry.

[13]  David Zurakowski,et al.  Inhibition of plaque neovascularization reduces macrophage accumulation and progression of advanced atherosclerosis , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[14]  M. Seishima,et al.  Lack of Interleukin-1&bgr; Decreases the Severity of Atherosclerosis in ApoE-Deficient Mice , 2003, Arteriosclerosis, thrombosis, and vascular biology.

[15]  D. Shih,et al.  Paraoxonase (PON1) deficiency is associated with increased macrophage oxidative stress: studies in PON1-knockout mice. , 2003, Free radical biology & medicine.

[16]  Jing Ma,et al.  Supplementation of diets with the black rice pigment fraction attenuates atherosclerotic plaque formation in apolipoprotein e deficient mice. , 2003, The Journal of nutrition.

[17]  Mark M. Kockx,et al.  Phagocytosis and Macrophage Activation Associated With Hemorrhagic Microvessels in Human Atherosclerosis , 2003, Arteriosclerosis, thrombosis, and vascular biology.

[18]  P. Debré,et al.  Decreased Atherosclerotic Lesion Formation in CX3CR1/Apolipoprotein E Double Knockout Mice , 2003, Circulation.

[19]  Z. Fayad,et al.  Characterization of aortic root atherosclerosis in ApoE knockout mice: High‐resolution in vivo and ex vivo MRM with histological correlation , 2003, Magnetic resonance in medicine.

[20]  Robert V Farese,et al.  Deficiency of acyl CoA:cholesterol acyltransferase 2 prevents atherosclerosis in apolipoprotein E-deficient mice , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[21]  E. Raines,et al.  Gene therapy of apolipoprotein E-deficient mice using a novel macrophage-specific retroviral vector. , 2003, Blood.

[22]  M. Ravid,et al.  Rosiglitazone (PPARγ‐agonist) attenuates atherogenesis with no effect on hyperglycaemia in a combined diabetes–atherosclerosis mouse model , 2003, Diabetes, obesity & metabolism.

[23]  R. Coleman,et al.  Oral Insulin Supplementation Attenuates Atherosclerosis Progression in Apolipoprotein E-Deficient Mice , 2003, Arteriosclerosis, thrombosis, and vascular biology.

[24]  Aldons J. Lusis,et al.  Identification of macrophage liver X receptors as inhibitors of atherosclerosis , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[25]  B. McManus,et al.  Increased ABCA1 activity protects against atherosclerosis. , 2002, The Journal of clinical investigation.

[26]  T. Willson,et al.  Synthetic LXR ligand inhibits the development of atherosclerosis in mice , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[27]  S. Zuckerman,et al.  Peroxisome proliferator-activated receptor α,γ coagonist LY465608 inhibits macrophage activation and atherosclerosis in apolipoprotein E knockout mice , 2002, Lipids.

[28]  Hong Yang,et al.  Dietary restriction reduces atherosclerosis and oxidative stress in the aorta of apolipoprotein E-deficient mice , 2002, Mechanisms of Ageing and Development.

[29]  T. V. van Berkel,et al.  Induction of Atherosclerotic Plaque Rupture in Apolipoprotein E−/− Mice After Adenovirus-Mediated Transfer of p53 , 2002, Circulation.

[30]  O. Francone,et al.  Increased Atherosclerosis in Hyperlipidemic Mice With Inactivation of ABCA1 in Macrophages , 2002, Arteriosclerosis, thrombosis, and vascular biology.

[31]  Akira Takeshita,et al.  Anti-Monocyte Chemoattractant Protein-1 Gene Therapy Limits Progression and Destabilization of Established Atherosclerosis in Apolipoprotein E–Knockout Mice , 2002, Circulation.

[32]  N. Maeda,et al.  Vulnerable Atherosclerotic Plaque Morphology in Apolipoprotein E-Deficient Mice Unable to Make Ascorbic Acid , 2002, Circulation.

[33]  A. Luttun,et al.  Lack of Plasminogen Activator Inhibitor-1 Promotes Growth and Abnormal Matrix Remodeling of Advanced Atherosclerotic Plaques in Apolipoprotein E–Deficient Mice , 2002, Arteriosclerosis, thrombosis, and vascular biology.

[34]  M. Krieger,et al.  Loss of SR-BI Expression Leads to the Early Onset of Occlusive Atherosclerotic Coronary Artery Disease, Spontaneous Myocardial Infarctions, Severe Cardiac Dysfunction, and Premature Death in Apolipoprotein E-Deficient Mice , 2002, Circulation research.

[35]  E. Falk,et al.  No Effect of Cyclooxygenase Inhibition on Plaque Size in Atherosclerosis-prone Mice , 2002, Scandinavian cardiovascular journal : SCJ.

[36]  R. F. Hoyt,et al.  The ATP binding cassette transporter A1 (ABCA1) modulates the development of aortic atherosclerosis in C57BL/6 and apoE-knockout mice , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[37]  C. Napoli,et al.  Chronic treatment with sulfhydryl angiotensin-converting enzyme inhibitors reduce susceptibility of plasma LDL to in vitro oxidation, formation of oxidation-specific epitopes in the arterial wall, and atherogenesis in apolipoprotein E knockout mice. , 2001, International journal of cardiology.

[38]  H. Davis,et al.  Ezetimibe, a Potent Cholesterol Absorption Inhibitor, Inhibits the Development of Atherosclerosis in ApoE Knockout Mice , 2001, Arteriosclerosis, thrombosis, and vascular biology.

[39]  E. Fisher,et al.  Elevating High-Density Lipoprotein Cholesterol in Apolipoprotein E—Deficient Mice Remodels Advanced Atherosclerotic Lesions by Decreasing Macrophage and Increasing Smooth Muscle Cell Content , 2001, Circulation.

[40]  M. Linton,et al.  Increased Cholesterol Efflux in Apolipoprotein AI (ApoAI)–Producing Macrophages as a Mechanism for Reduced Atherosclerosis in ApoAI(−/−) Mice , 2001, Arteriosclerosis, thrombosis, and vascular biology.

[41]  R. Cohen,et al.  S17834, a New Inhibitor of Cell Adhesion and Atherosclerosis That Targets NADPH Oxidase , 2001, Arteriosclerosis, thrombosis, and vascular biology.

[42]  E. Falk,et al.  Dietary Supplementation With Methionine and Homocysteine Promotes Early Atherosclerosis but Not Plaque Rupture in ApoE-Deficient Mice , 2001, Arteriosclerosis, thrombosis, and vascular biology.

[43]  S. Ishibashi,et al.  Direct effect of an acyl‐CoA:cholesterol acyltransferase inhibitor, F‐1394, on atherosclerosis in apolipoprotein E and low density lipoprotein receptor double knockout mice , 2001, British journal of pharmacology.

[44]  R. Coleman,et al.  Pomegranate juice supplementation to atherosclerotic mice reduces macrophage lipid peroxidation, cellular cholesterol accumulation and development of atherosclerosis. , 2001, The Journal of nutrition.

[45]  Paul L Huang,et al.  Accelerated Atherosclerosis, Aortic Aneurysm Formation, and Ischemic Heart Disease in Apolipoprotein E/Endothelial Nitric Oxide Synthase Double-Knockout Mice , 2001, Circulation.

[46]  C. Schindler,et al.  Lymphocytes are important in early atherosclerosis. , 2001, The Journal of clinical investigation.

[47]  J. Astern,et al.  Genetic Deficiency of Inducible Nitric Oxide Synthase Reduces Atherosclerosis and Lowers Plasma Lipid Peroxides in Apolipoprotein E–Knockout Mice , 2001, Circulation.

[48]  R. Leboeuf,et al.  Iron overload diminishes atherosclerosis in apoE-deficient mice. , 2001, The Journal of clinical investigation.

[49]  J. Badimón,et al.  Acyl-CoA:Cholesterol Acyltransferase Inhibition Reduces Atherosclerosis in Apolipoprotein E—Deficient Mice , 2001, Circulation.

[50]  A. Borczuk,et al.  ApoE knockout mice expressing human matrix metalloproteinase-1 in macrophages have less advanced atherosclerosis. , 2001, The Journal of clinical investigation.

[51]  D. Rader,et al.  Absence of 12/15-Lipoxygenase Expression Decreases Lipid Peroxidation and Atherogenesis in Apolipoprotein E—Deficient Mice , 2001, Circulation.

[52]  J. Jukema,et al.  Its Cholesterol-Lowering Effect in ApoE * 3-Leiden Mice Acyl-CoA : Cholesterol Acyltransferase Inhibitor Avasimibe Reduces Atherosclerosis in Addition to , 2001 .

[53]  E. Falk,et al.  Red Wine Does Not Reduce Mature Atherosclerosis in Apolipoprotein E –Deficient Mice , 2001, Circulation.

[54]  RyozoNagai,et al.  Troglitazone Inhibits Atherosclerosis in Apolipoprotein E–Knockout Mice , 2001 .

[55]  S. Perrey,et al.  Troglitazone Inhibits Atherosclerosis in Apolipoprotein E–Knockout Mice: Pleiotropic Effects on CD36 Expression and HDL , 2001, Arteriosclerosis, thrombosis, and vascular biology.

[56]  D. Mangelsdorf,et al.  LXRs control lipid-inducible expression of the apolipoprotein E gene in macrophages and adipocytes. , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[57]  J. Joven,et al.  The continuous administration of aspirin attenuates atherosclerosis in apolipoprotein E-deficient mice. , 2000, Life sciences.

[58]  Robert V Farese,et al.  Increased atherosclerosis in hyperlipidemic mice deficient in alpha -tocopherol transfer protein and vitamin E. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[59]  Stephen M. Schwartz,et al.  Advanced Atherosclerotic Lesions in the Innominate Artery of the ApoE Knockout Mouse , 2000, Arteriosclerosis, thrombosis, and vascular biology.

[60]  T. V. van Berkel,et al.  Effect of Human Scavenger Receptor Class A Overexpression in Bone Marrow–Derived Cells on Cholesterol Levels and Atherosclerosis in ApoE-Deficient Mice , 2000, Arteriosclerosis, thrombosis, and vascular biology.

[61]  C. Cordon-Cardo,et al.  Sulindac inhibits neointimal formation after arterial injury in wild-type and apolipoprotein E-deficient mice. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[62]  D. Shih,et al.  Combined Serum Paraoxonase Knockout/Apolipoprotein E Knockout Mice Exhibit Increased Lipoprotein Oxidation and Atherosclerosis* , 2000, The Journal of Biological Chemistry.

[63]  L. Curtiss,et al.  Apolipoprotein E and atherosclerosis. , 2000, Current opinion in lipidology.

[64]  D. Wagner,et al.  Prominent role of P-selectin in the development of advanced atherosclerosis in ApoE-deficient mice. , 2000, Circulation.

[65]  S. Hazen,et al.  Targeted disruption of the class B scavenger receptor CD36 protects against atherosclerotic lesion development in mice. , 2000, The Journal of clinical investigation.

[66]  J. Breslow,et al.  Apolipoprotein E regulates dietary cholesterol absorption and biliary cholesterol excretion: studies in C57BL/6 apolipoprotein E knockout mice. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[67]  Robert V Farese,et al.  Massive xanthomatosis and altered composition of atherosclerotic lesions in hyperlipidemic mice lacking acyl CoA:cholesterol acyltransferase 1. , 2000, The Journal of clinical investigation.

[68]  E. Nabel,et al.  Atherosclerosis progression in LDL receptor-deficient and apolipoprotein E-deficient mice is independent of genetic alterations in plasminogen activator inhibitor-1. , 2000, Arteriosclerosis, thrombosis, and vascular biology.

[69]  J. Joven,et al.  Low-cholesterol and high-fat diets reduce atherosclerotic lesion development in ApoE-knockout mice. , 1999, Arteriosclerosis, thrombosis, and vascular biology.

[70]  M. Halks-Miller,et al.  Accelerated atherosclerosis and premature calcified cartilaginous metaplasia in the aorta of diabetic male Apo E knockout mice can be prevented by chronic treatment with 17 beta-estradiol. , 1999, Atherosclerosis.

[71]  M A Konerding,et al.  Angiogenesis inhibitors endostatin or TNP-470 reduce intimal neovascularization and plaque growth in apolipoprotein E-deficient mice. , 1999, Circulation.

[72]  Tzong-Shyuan Lee,et al.  Iron-deficient diet reduces atherosclerotic lesions in apoE-deficient mice. , 1999, Circulation.

[73]  P. Denéfle,et al.  Somatic gene transfer of human ApoA-I inhibits atherosclerosis progression in mouse models. , 1999, Circulation.

[74]  E A Fisher,et al.  Noninvasive In vivo high-resolution magnetic resonance imaging of atherosclerotic lesions in genetically engineered mice. , 1998, Circulation.

[75]  D. Rader,et al.  Vitamin E suppresses isoprostane generation in vivo and reduces atherosclerosis in ApoE-deficient mice , 1998, Nature Medicine.

[76]  P. Libby,et al.  Macrophages in Human Atheroma Contain PPARγ: Differentiation-Dependent Peroxisomal Proliferator-Activated Receptor γ (PPARγ) Expression and Reduction of MMP-9 Activity through PPARγ Activation in Mononuclear Phagocytes in Vitro , 1998 .

[77]  J. Breslow,et al.  Antiatherosclerotic and antioxidative effects of captopril in apolipoprotein E-deficient mice. , 1998, Journal of cardiovascular pharmacology.

[78]  D. Witte,et al.  Fibrinogen deficiency is compatible with the development of atherosclerosis in mice. , 1998, The Journal of clinical investigation.

[79]  D. Heistad,et al.  Atherosclerosis, vascular remodeling, and impairment of endothelium-dependent relaxation in genetically altered hyperlipidemic mice. , 1997, Arteriosclerosis, thrombosis, and vascular biology.

[80]  J. Arnal,et al.  17β-Estradiol Prevents Fatty Streak Formation in Apolipoprotein E–Deficient Mice , 1997 .

[81]  G. Hansson.  Cell-mediated immunity in atherosclerosis , 1997, Current opinion in lipidology.

[82]  D. Witte,et al.  Plasminogen deficiency accelerates vessel wall disease in mice predisposed to atherosclerosis. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[83]  A Daugherty,et al.  The effects of total lymphocyte deficiency on the extent of atherosclerosis in apolipoprotein E-/- mice. , 1997, The Journal of clinical investigation.

[84]  Daniel Steinberg,et al.  Low Density Lipoprotein Oxidation and Its Pathobiological Significance* , 1997, The Journal of Biological Chemistry.

[85]  J. Breslow,et al.  The angiotensin-II receptor antagonist, losartan, inhibits LDL lipid peroxidation and atherosclerosis in apolipoprotein E-deficient mice. , 1997, Biochemical and biophysical research communications.

[86]  N. Maeda,et al.  Hepatic Lipase Deficiency Increases Plasma Cholesterol but Reduces Susceptibility to Atherosclerosis in Apolipoprotein E-deficient Mice* , 1997, The Journal of Biological Chemistry.

[87]  Yukiko Kurihara,et al.  A role for macrophage scavenger receptors in atherosclerosis and susceptibility to infection , 1997, Nature.

[88]  P. Milos,et al.  Estrogen reduces atherosclerotic lesion development in apolipoprotein E-deficient mice. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[89]  E M Rubin,et al.  Quantitation of atherosclerosis in murine models: correlation between lesions in the aortic origin and in the entire aorta, and differences in the extent of lesions between sexes in LDL receptor-deficient and apolipoprotein E-deficient mice. , 1995, Journal of lipid research.

[90]  M. Aviram,et al.  Iron induces lipid peroxidation in cultured macrophages, increases their ability to oxidatively modify LDL, and affects their secretory properties. , 1994, Atherosclerosis.

[91]  E. Rubin,et al.  Apolipoprotein AI transgene corrects apolipoprotein E deficiency-induced atherosclerosis in mice. , 1994, The Journal of clinical investigation.

[92]  N. Maeda,et al.  Spontaneous hypercholesterolemia and arterial lesions in mice lacking apolipoprotein E. , 1992, Science.

[93]  E. Rubin,et al.  Severe hypercholesterolemia and atherosclerosis in apolipoprotein E-deficient mice created by homologous recombination in ES cells , 1992, Cell.

[94]  N. Maeda,et al.  Generation of mice carrying a mutant apolipoprotein E gene inactivated by gene targeting in embryonic stem cells. , 1992, Proceedings of the National Academy of Sciences of the United States of America.

[95]  R. Williams,et al.  Quantitative assessment of atherosclerotic lesions in mice. , 1987, Atherosclerosis.

[96]  R. Stocker,et al.  Dealcoholized red wine decreases atherosclerosis in apolipoprotein E gene-deficient mice independently of inhibition of lipid peroxidation in the artery wall. , 2004, The American journal of clinical nutrition.

[97]  I. Puddey,et al.  Red wine polyphenolic compounds inhibit atherosclerosis in apolipoprotein E-deficient mice independently of effects on lipid peroxidation. , 2004, The American journal of clinical nutrition.

[98]  T. Gjøen,et al.  Hepatic scavenger receptor class B, type I is stimulated by peroxisome proliferator-activated receptor gamma and hepatocyte nuclear factor 4alpha. , 2003, Biochemical and biophysical research communications.

[99]  J. Michel,et al.  Interleukin-10 Deficiency Increases Atherosclerosis, Thrombosis, and Low-density Lipoproteins in Apolipoprotein E Knockout Mice , 2003, Molecular medicine.

[100]  Andreas Schober,et al.  Circulating activated platelets exacerbate atherosclerosis in mice deficient in apolipoprotein E , 2003, Nature Medicine.

[101]  J. Alvarez‐Leite,et al.  Monocyte chemoattractant protein-1 involvement in the alpha-tocopherol-induced reduction of atherosclerotic lesions in apolipoprotein E knockout mice. , 2003, The British journal of nutrition.

[102]  S. Zuckerman,et al.  Peroxisome proliferator-activated receptor alpha,gamma coagonist LY465608 inhibits macrophage activation and atherosclerosis in apolipoprotein E knockout mice. , 2002, Lipids.

[103]  P. Libby,et al.  Macrophages in human atheroma contain PPARgamma: differentiation-dependent peroxisomal proliferator-activated receptor gamma(PPARgamma) expression and reduction of MMP-9 activity through PPARgamma activation in mononuclear phagocytes in vitro. , 1998, The American journal of pathology.

[104]  R. Ross,et al.  ApoE-deficient mice develop lesions of all phases of atherosclerosis throughout the arterial tree. , 1994, Arteriosclerosis and thrombosis : a journal of vascular biology.

[105]  N. Maeda,et al.  Atherosclerosis in mice lacking apo E. Evaluation of lesional development and progression. , 1994, Arteriosclerosis and thrombosis : a journal of vascular biology.