title: Loss of Reelin protects against atherosclerosis by reducing leukocyte-endothelial cell adhesion and lesion macrophage accumulation.
abstract: The multimodular glycoprotein Reelin controls neuronal migration and synaptic transmission by binding to apolipoprotein E receptor 2 (Apoer2) and very low density lipoprotein receptor (Vldlr) on neurons. In the periphery, Reelin is produced by the liver, circulates in blood, and promotes thrombosis and hemostasis. To investigate if Reelin influences atherogenesis, we studied atherosclerosis-prone low-density lipoprotein receptor-deficient (Ldlr(-/-)) mice in which we inducibly deleted Reelin either ubiquitously or only in the liver, thus preventing the production of circulating Reelin. In both types of Reelin-deficient mice, atherosclerosis progression was markedly attenuated, and macrophage content and endothelial cell staining for vascular cell adhesion molecule-1 (VCAM-1) and intercellular adhesion molecule-1 (ICAM-1) were reduced at the sites of atherosclerotic lesions. Intravital microscopy revealed decreased leukocyte-endothelial adhesion in the Reelin-deficient mice. In cultured human endothelial cells, Reelin enhanced monocyte adhesion and increased ICAM1, VCAM1, and E-selectin expression by suppressing endothelial nitric oxide synthase (eNOS) activity and increasing nuclear factor κB (NF-κB) activity in an Apoer2-dependent manner. These findings suggest that circulating Reelin promotes atherosclerosis by increasing vascular inflammation, and that reducing or inhibiting circulating Reelin may present a novel approach for the prevention of cardiovascular disease.
authors.affiliation: Department of Molecular Genetics, University of Texas (UT) Southwestern Medical Center, Dallas, TX 75390, USA. Center for Translational Neurodegeneration Research, UT Southwestern Medical Center, Dallas, TX 75390, USA. Key Laboratory of Medical Electrophysiology, Ministry of Education of China, and the Institute of Cardiovascular Research, Sichuan Medical University, Luzhou 646000, China.
authors.forename: Yinyuan
authors.initials: Y
authors.lastname: Ding
authors.affiliation: Center for Pulmonary and Vascular Biology, Department of Pediatrics, UT Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Linzhang
authors.initials: L
authors.lastname: Huang
authors.affiliation: Department of Molecular Genetics, University of Texas (UT) Southwestern Medical Center, Dallas, TX 75390, USA. Center for Translational Neurodegeneration Research, UT Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Xunde
authors.initials: X
authors.lastname: Xian
authors.affiliation: Center for Pulmonary and Vascular Biology, Department of Pediatrics, UT Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Ivan S
authors.initials: IS
authors.lastname: Yuhanna
authors.affiliation: Department of Molecular Genetics, University of Texas (UT) Southwestern Medical Center, Dallas, TX 75390, USA. Center for Translational Neurodegeneration Research, UT Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Catherine R
authors.initials: CR
authors.lastname: Wasser
authors.affiliation: Zentrum für Molekulare Neurobiologie Hamburg, Falkenried 94, 20251 Hamburg, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Frotscher
authors.affiliation: Center for Pulmonary and Vascular Biology, Department of Pediatrics, UT Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Chieko
authors.initials: C
authors.lastname: Mineo
authors.affiliation: Center for Pulmonary and Vascular Biology, Department of Pediatrics, UT Southwestern Medical Center, Dallas, TX 75390, USA. philip.shaul@utsouthwestern.edu joachim.herz@utsouthwestern.edu.
authors.forename: Philip W
authors.initials: PW
authors.lastname: Shaul
authors.affiliation: Department of Molecular Genetics, University of Texas (UT) Southwestern Medical Center, Dallas, TX 75390, USA. Center for Translational Neurodegeneration Research, UT Southwestern Medical Center, Dallas, TX 75390, USA. Department of Neuroscience, UT Southwestern Medical Center, Dallas, TX 75390, USA. Department of Neurology and Neurotherapeutics, UT Southwestern Medical Center, Dallas, TX 75390, USA. Center for Neuroscience, Department of Neuroanatomy, Albert-Ludwigs-University, 79104 Freiburg, Germany. philip.shaul@utsouthwestern.edu joachim.herz@utsouthwestern.edu.
authors.forename: Joachim
authors.initials: J
authors.lastname: Herz
mesh_terms: D000818:Animals; D050197:Atherosclerosis / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control; D002448:Cell Adhesion; D015816:Cell Adhesion Molecules, Neuronal / Q000235:genetics / Q000378:metabolism*; D019040:E-Selectin / Q000235:genetics / Q000378:metabolism; D042783:Endothelial Cells / Q000378:metabolism* / Q000473:pathology; D016326:Extracellular Matrix Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics / Q000378:metabolism*; D026502:LDL-Receptor Related Proteins / Q000235:genetics / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D000091042:Reelin Protein; D012697:Serine Endopeptidases / Q000235:genetics / Q000378:metabolism*; D019010:Vascular Cell Adhesion Molecule-1 / Q000235:genetics / Q000378:metabolism*
chemical_list: D015816:Cell Adhesion Molecules, Neuronal; D019040:E-Selectin; D016326:Extracellular Matrix Proteins; C573420:ICAM1 protein, human; C090509:Icam1 protein, mouse; D026502:LDL-Receptor Related Proteins; D016328:NF-kappa B; D009419:Nerve Tissue Proteins; D000091042:Reelin Protein; D019010:Vascular Cell Adhesion Molecule-1; C098773:low density lipoprotein receptor-related protein 8; D018799:Intercellular Adhesion Molecule-1; C000717127:RELN protein, human; C000717128:Reln protein, mouse; D012697:Serine Endopeptidases