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Trends in Pharmacological Sciences
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Mouse models of atherosclerosis in translational research

  • Iqra Ilyas
    Affiliations
    Department of Endocrinology, Institute of Endocrine and Metabolic Diseases, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, Clinical Research Hospital of Chinese Academy of Sciences (Hefei), University of Science and Technology of China, Hefei, China
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  • Peter J. Little
    Affiliations
    School of Pharmacy, University of Queensland, Pharmacy Australia Centre of Excellence, Woolloongabba, QLD, Australia
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  • Zhiping Liu
    Affiliations
    Guangdong Province Key Laboratory of Pharmacodynamic Constituents of Traditional Chinese Medicine and New Drugs Research, College of Pharmacy, Jinan University, Guangzhou, China
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  • Yanyong Xu
    Affiliations
    Key Laboratory of Metabolism and Molecular Medicine of the Ministry of Education, Department of Pathology of School of Basic Medical Sciences, Fudan University, Shanghai, China
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  • Danielle Kamato
    Affiliations
    School of Pharmacy, University of Queensland, Pharmacy Australia Centre of Excellence, Woolloongabba, QLD, Australia

    Griffith Institute for Drug Discovery, School of Environment and Science, Griffith University, Brisbane, Australia
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  • Bradford C. Berk
    Affiliations
    Aab Cardiovascular Research Institute, Department of Medicine, University of Rochester School of Medicine and Dentistry, Rochester, NY, USA
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  • Jianping Weng
    Correspondence
    Correspondence:
    Affiliations
    Department of Endocrinology, Institute of Endocrine and Metabolic Diseases, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, Clinical Research Hospital of Chinese Academy of Sciences (Hefei), University of Science and Technology of China, Hefei, China

    Laboratory of Metabolics and Cardiovascular Diseases, Institute of Endocrine and Metabolic Diseases, University of Science and Technology of China, Hefei, China

    Biomedical Sciences and Health Laboratory of Anhui Province, University of Science and Technology of China, Hefei, China
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  • Suowen Xu
    Correspondence
    Correspondence:
    Affiliations
    Department of Endocrinology, Institute of Endocrine and Metabolic Diseases, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, Clinical Research Hospital of Chinese Academy of Sciences (Hefei), University of Science and Technology of China, Hefei, China

    Laboratory of Metabolics and Cardiovascular Diseases, Institute of Endocrine and Metabolic Diseases, University of Science and Technology of China, Hefei, China

    Biomedical Sciences and Health Laboratory of Anhui Province, University of Science and Technology of China, Hefei, China
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      Highlights

      • A similar lipid profile and disease pathology are important considerations for selecting mouse model of atherosclerosis for translational research.
      • Apoe−/− mice, Ldlr−/− mice, and APOE3-Leiden.CETP mice are important preclinical models that have been used to validate FDA-approved lipid-lowering drugs.
      • AAV8-Pcsk9-D377Y injection can induce atherosclerotic plaque formation in C57BL/6J mice without crossbreeding with atherosusceptible mouse strains.
      • Partial carotid ligation surgery in Apoe−/− mice or Ldlr−/− mice creates flow disturbance and emerges as a new model to examine the role of mechanosensitive factors in atherogenesis.
      Atherosclerotic cardiovascular disease (CVD), the major cause of premature human mortality, is a chronic and progressive metabolic and inflammatory disease in large- and medium-sized arteries. Mouse models are widely used to gain mechanistic insights into the pathogenesis of atherosclerosis and have facilitated the discovery of anti-atherosclerotic drugs. Despite promising preclinical studies, many drug candidates have not translated to clinical use because of the complexity of disease patho-mechanisms including lipid metabolic traits and inflammatory, genetic, and hemodynamic factors. We review the current preclinical utility and translation potential of traditional [apolipoprotein E (APOE)- and low-density lipoprotein (LDL) receptor (LDLR)-deficient mice] and emerging mouse models that include partial carotid ligation and AAV8-Pcsk9-D377Y injection in atherosclerosis research and drug discovery. This article represents an important resource in atherosclerosis research.

      Keywords

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      Glossary

      Apolipoprotein E (APOE)
      a structural component of all lipoproteins except LDL; it binds to the LDL receptor, the VLDL receptor, and related proteins in the liver to facilitate the clearance of plasma chylomicrons and VLDL remnants.
      Atherosclerosis
      a multifactorial, progressive, and chronic inflammatory disease characterized by the accumulation and retention of LDL and its modified form in the arterial wall.
      Chylomicrons
      the largest and most buoyant class of lipoproteins, with diameters of 75–600 nm.
      Disturbed blood flow (d-flow)
      d-flow occurs at the regions of arterial branches and inner curvature of the aortic arch or at vessel bifurcations. As a result, d-flow induces a sustained activation of endothelial cells (ECs), a hallmark characteristic of atherosclerosis.
      Low-density lipoprotein (LDL) receptor (LDLR)
      a membrane receptor which mediates the endocytosis of LDL cholesterol (LDL-C) from the blood into hepatocytes and thus maintains the plasma level of LDL.
      Partial carotid ligation (PCL)
      an acute model of vascular remodeling and atherosclerosis induced by flow disturbance. In this model, three branches of the left common carotid artery (LCA) are ligated, while leaving the superior thyroid artery open. PCL causes d-flow that is intimately associated with endothelial dysfunction and atherogenesis.
      Proprotein convertase subtilisin/kexin type 9 (PCSK9)
      an enzyme encoded by the PCSK9 gene. It binds to LDLR and promotes its degradation in the lysosome. PSCK9 represents a promising therapeutic target in cardiovascular disease. Currently, monoclonal antibodies, siRNA, antisense oligonucleotide, and small-molecule inhibitors of PSCK9 are being developed for therapeutic purposes.
      Vascular tree
      the whole-body network of blood vessels, including arteries, veins, capillaries, and lymphatic vessels, that allow the blood to circulate and perfuse in the body.
      Very low density lipoprotein (VLDL)
      a type of lipoprotein made by liver which is less dense than high-density lipoprotein (HDL) and contains more cholesterol.
      Vulnerable atherosclerotic plaque
      a type of atheromatous plaque that has thin fibrous cap, large necrotic core, pronounced inflammation, intensive neovascularization, intraplaque hemorrhage, and calcification; this type of plaque is prone to sudden rupture and can cause heart attack or ischemic stroke.