title: Poliovirus Receptor-Related 2: A Cholesterol-Responsive Gene Affecting Atherosclerosis Development by Modulating Leukocyte Migration.
abstract: OBJECTIVE
  Recently, poliovirus receptor-related 2 (Pvrl2) emerged as a top gene in a global gene expression study aiming to detect plasma cholesterol-responsive genes causally related to atherosclerosis regression in hypercholesterolemic mice. PVRL2 is an adherens junction protein implied to play a role in transendothelial migration of leukocytes, a key feature in atherosclerosis development. In this study, we investigated the effect ofPvrl2deficiency on atherosclerosis development and transendothelial migration of leukocytes activity. APPROACH AND RESULTS:Pvrl2-deficient mice bred onto an atherosclerosis-prone background (Pvrl2-/-Ldlr-/-Apob100/100) had less atherosclerotic lesions and more stable plaques compared with littermate controls (Pvrl2+/+Ldlr-/-Apob100/100).Pvrl2-/-Ldlr-/-Apob100/100mice also showed a 49% decrease in transendothelial migration of leukocytes activity observed using the in vivo air pouch model. In accordance, augmented arterial wall expression ofPvrl2during atherosclerosis progression coincided with an increased gene expression of migrating leukocytes into the vessel wall. Both in human and mice, gene and protein expression of PVRL2 was predominantly observed in the vascular endothelium according to the immunohistochemical and gene expression data. In addition, the cholesterol responsiveness ofPVRL2was also observed in humans.
  
  
  CONCLUSIONS
  PVRL2 is a plasma cholesterol-responsive gene acting at endothelial sites of vascular inflammation that could potentially be a new therapeutic target for atherosclerosis prevention through its suggested transendothelial migration of leukocytes modulating activity.
authors.affiliation: From the Division of Vascular Biology, Department of Medical Biochemistry and Biophysics (A.R., H.G., C.M., H.F.A., H.A.T., J.L.M.B., E.F., J.S.) and Unit of Computational Medicine, Department of Medicine (M.-M.S.), Karolinska Institutet, Stockholm, Sweden; Department of Genetics and Genomic Sciences, Institute of Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY (O.F., J.L.M.B.); and Department of Molecular Genetics and Microbiology, Stony Brook University, New York, NY (S.M.). Erika.folestad@ki.se Aranzazu.rossignoli@ki.se.
authors.forename: Aránzazu
authors.initials: A
authors.lastname: Rossignoli
authors.affiliation: From the Division of Vascular Biology, Department of Medical Biochemistry and Biophysics (A.R., H.G., C.M., H.F.A., H.A.T., J.L.M.B., E.F., J.S.) and Unit of Computational Medicine, Department of Medicine (M.-M.S.), Karolinska Institutet, Stockholm, Sweden; Department of Genetics and Genomic Sciences, Institute of Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY (O.F., J.L.M.B.); and Department of Molecular Genetics and Microbiology, Stony Brook University, New York, NY (S.M.).
authors.forename: Ming-Mei
authors.initials: MM
authors.lastname: Shang
authors.affiliation: From the Division of Vascular Biology, Department of Medical Biochemistry and Biophysics (A.R., H.G., C.M., H.F.A., H.A.T., J.L.M.B., E.F., J.S.) and Unit of Computational Medicine, Department of Medicine (M.-M.S.), Karolinska Institutet, Stockholm, Sweden; Department of Genetics and Genomic Sciences, Institute of Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY (O.F., J.L.M.B.); and Department of Molecular Genetics and Microbiology, Stony Brook University, New York, NY (S.M.).
authors.forename: Hanna
authors.initials: H
authors.lastname: Gladh
authors.affiliation: From the Division of Vascular Biology, Department of Medical Biochemistry and Biophysics (A.R., H.G., C.M., H.F.A., H.A.T., J.L.M.B., E.F., J.S.) and Unit of Computational Medicine, Department of Medicine (M.-M.S.), Karolinska Institutet, Stockholm, Sweden; Department of Genetics and Genomic Sciences, Institute of Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY (O.F., J.L.M.B.); and Department of Molecular Genetics and Microbiology, Stony Brook University, New York, NY (S.M.).
authors.forename: Christine
authors.initials: C
authors.lastname: Moessinger
authors.affiliation: From the Division of Vascular Biology, Department of Medical Biochemistry and Biophysics (A.R., H.G., C.M., H.F.A., H.A.T., J.L.M.B., E.F., J.S.) and Unit of Computational Medicine, Department of Medicine (M.-M.S.), Karolinska Institutet, Stockholm, Sweden; Department of Genetics and Genomic Sciences, Institute of Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY (O.F., J.L.M.B.); and Department of Molecular Genetics and Microbiology, Stony Brook University, New York, NY (S.M.).
authors.forename: Hassan
authors.initials: H
authors.lastname: Foroughi Asl
authors.affiliation: From the Division of Vascular Biology, Department of Medical Biochemistry and Biophysics (A.R., H.G., C.M., H.F.A., H.A.T., J.L.M.B., E.F., J.S.) and Unit of Computational Medicine, Department of Medicine (M.-M.S.), Karolinska Institutet, Stockholm, Sweden; Department of Genetics and Genomic Sciences, Institute of Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY (O.F., J.L.M.B.); and Department of Molecular Genetics and Microbiology, Stony Brook University, New York, NY (S.M.).
authors.forename: Husain Ahammad
authors.initials: HA
authors.lastname: Talukdar
authors.affiliation: From the Division of Vascular Biology, Department of Medical Biochemistry and Biophysics (A.R., H.G., C.M., H.F.A., H.A.T., J.L.M.B., E.F., J.S.) and Unit of Computational Medicine, Department of Medicine (M.-M.S.), Karolinska Institutet, Stockholm, Sweden; Department of Genetics and Genomic Sciences, Institute of Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY (O.F., J.L.M.B.); and Department of Molecular Genetics and Microbiology, Stony Brook University, New York, NY (S.M.).
authors.forename: Oscar
authors.initials: O
authors.lastname: Franzén
authors.affiliation: From the Division of Vascular Biology, Department of Medical Biochemistry and Biophysics (A.R., H.G., C.M., H.F.A., H.A.T., J.L.M.B., E.F., J.S.) and Unit of Computational Medicine, Department of Medicine (M.-M.S.), Karolinska Institutet, Stockholm, Sweden; Department of Genetics and Genomic Sciences, Institute of Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY (O.F., J.L.M.B.); and Department of Molecular Genetics and Microbiology, Stony Brook University, New York, NY (S.M.).
authors.forename: Steffen
authors.initials: S
authors.lastname: Mueller
authors.affiliation: From the Division of Vascular Biology, Department of Medical Biochemistry and Biophysics (A.R., H.G., C.M., H.F.A., H.A.T., J.L.M.B., E.F., J.S.) and Unit of Computational Medicine, Department of Medicine (M.-M.S.), Karolinska Institutet, Stockholm, Sweden; Department of Genetics and Genomic Sciences, Institute of Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY (O.F., J.L.M.B.); and Department of Molecular Genetics and Microbiology, Stony Brook University, New York, NY (S.M.).
authors.forename: Johan L M
authors.initials: JL
authors.lastname: Björkegren
authors.affiliation: From the Division of Vascular Biology, Department of Medical Biochemistry and Biophysics (A.R., H.G., C.M., H.F.A., H.A.T., J.L.M.B., E.F., J.S.) and Unit of Computational Medicine, Department of Medicine (M.-M.S.), Karolinska Institutet, Stockholm, Sweden; Department of Genetics and Genomic Sciences, Institute of Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY (O.F., J.L.M.B.); and Department of Molecular Genetics and Microbiology, Stony Brook University, New York, NY (S.M.).
authors.forename: Erika
authors.initials: E
authors.lastname: Folestad
authors.affiliation: From the Division of Vascular Biology, Department of Medical Biochemistry and Biophysics (A.R., H.G., C.M., H.F.A., H.A.T., J.L.M.B., E.F., J.S.) and Unit of Computational Medicine, Department of Medicine (M.-M.S.), Karolinska Institutet, Stockholm, Sweden; Department of Genetics and Genomic Sciences, Institute of Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY (O.F., J.L.M.B.); and Department of Molecular Genetics and Microbiology, Stony Brook University, New York, NY (S.M.). Erika.folestad@ki.se Aranzazu.rossignoli@ki.se.
authors.forename: Josefin
authors.initials: J
authors.lastname: Skogsberg
mesh_terms: D000818:Animals; D001013:Aorta, Thoracic / Q000378:metabolism* / Q000473:pathology; D001018:Aortic Diseases / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D053299:Apolipoprotein B-100; D001055:Apolipoproteins B / Q000172:deficiency / Q000235:genetics; D050197:Atherosclerosis / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D002448:Cell Adhesion; D015815:Cell Adhesion Molecules / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D002784:Cholesterol / Q000097:blood*; D018920:Coculture Techniques; D004195:Disease Models, Animal; D018450:Disease Progression; D004730:Endothelium, Vascular / Q000378:metabolism* / Q000473:pathology; D020022:Genetic Predisposition to Disease; D061307:Human Umbilical Vein Endothelial Cells / Q000378:metabolism; D006801:Humans; D007962:Leukocytes / Q000378:metabolism*; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D000075983:Nectins; D010641:Phenotype; D034622:RNA Interference; D011973:Receptors, LDL / Q000172:deficiency / Q000235:genetics; D015398:Signal Transduction; D013997:Time Factors; D057705:Transendothelial and Transepithelial Migration; D014162:Transfection
chemical_list: C415826:Apob protein, mouse; D053299:Apolipoprotein B-100; D001055:Apolipoproteins B; D015815:Cell Adhesion Molecules; C000619016:Nectin2 protein, mouse; D000075983:Nectins; D011973:Receptors, LDL; D002784:Cholesterol
keywords: adherens junctions; atherosclerosis; cholesterol; coronary artery disease; inflammation; leukocyte migration