ArticleCirculation research2015
Differential role of an NF-κB transcriptional response element in endothelial versus intimal cell VCAM-1 expression.
Open access · bronzeAbstract readComparative Study
In one paragraph
Article in Circulation research, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 30 papers.
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30citing papers in PubMed
0.5field-weighted citation impact, top 35% of its field
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Who cites it
30 citing papers in PubMed, 50 citations in OpenAlex.
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Corrections and comments
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Authors and funding
15 authors at 5 institutions in 3 countries.
David S MilstoneFrom the Vascular Research Division, Department of Pathology, Center for Excellence in Vascular Biology (D.S.M., P.O.D., V.M.D., T.C.) and Cardiovascular Division (J.P., J.D.B.), Brigham and Women's Hospital and Harvard Medical School, Boston, MA; Advanced Diagnostics Division, Toronto General Research Institute, University Health Network Toronto, Ontario, Canada (M.I., M.C., A.S., A.C.L., S.-N.Z., M.F.B., J.J.-B., M.I.C.); Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada (M.I., M.C., A.S., A.C.L., S.-N.Z., M.F.B., J.J.-B., M.I.C.); Department of Geriatric Medicine, Kyoto University Hospital, Kyoto, Japan (M.I.); Case Cardiovascular Research Institute, Department of Medicine, Case Western Reserve University School of Medicine, Cleveland, OH (S.M.H.); and Department of Pathology, Children's Hospital and Harvard Medical School, Boston, MA (T.C.). myron.cybulsky@utoronto.ca milstone@rascal.med.harvard.edu.
Motoi IlyamaFrom the Vascular Research Division, Department of Pathology, Center for Excellence in Vascular Biology (D.S.M., P.O.D., V.M.D., T.C.) and Cardiovascular Division (J.P., J.D.B.), Brigham and Women's Hospital and Harvard Medical School, Boston, MA; Advanced Diagnostics Division, Toronto General Research Institute, University Health Network Toronto, Ontario, Canada (M.I., M.C., A.S., A.C.L., S.-N.Z., M.F.B., J.J.-B., M.I.C.); Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada (M.I., M.C., A.S., A.C.L., S.-N.Z., M.F.B., J.J.-B., M.I.C.); Department of Geriatric Medicine, Kyoto University Hospital, Kyoto, Japan (M.I.); Case Cardiovascular Research Institute, Department of Medicine, Case Western Reserve University School of Medicine, Cleveland, OH (S.M.H.); and Department of Pathology, Children's Hospital and Harvard Medical School, Boston, MA (T.C.).
Mian ChenFrom the Vascular Research Division, Department of Pathology, Center for Excellence in Vascular Biology (D.S.M., P.O.D., V.M.D., T.C.) and Cardiovascular Division (J.P., J.D.B.), Brigham and Women's Hospital and Harvard Medical School, Boston, MA; Advanced Diagnostics Division, Toronto General Research Institute, University Health Network Toronto, Ontario, Canada (M.I., M.C., A.S., A.C.L., S.-N.Z., M.F.B., J.J.-B., M.I.C.); Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada (M.I., M.C., A.S., A.C.L., S.-N.Z., M.F.B., J.J.-B., M.I.C.); Department of Geriatric Medicine, Kyoto University Hospital, Kyoto, Japan (M.I.); Case Cardiovascular Research Institute, Department of Medicine, Case Western Reserve University School of Medicine, Cleveland, OH (S.M.H.); and Department of Pathology, Children's Hospital and Harvard Medical School, Boston, MA (T.C.).
Peter O'DonnellFrom the Vascular Research Division, Department of Pathology, Center for Excellence in Vascular Biology (D.S.M., P.O.D., V.M.D., T.C.) and Cardiovascular Division (J.P., J.D.B.), Brigham and Women's Hospital and Harvard Medical School, Boston, MA; Advanced Diagnostics Division, Toronto General Research Institute, University Health Network Toronto, Ontario, Canada (M.I., M.C., A.S., A.C.L., S.-N.Z., M.F.B., J.J.-B., M.I.C.); Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada (M.I., M.C., A.S., A.C.L., S.-N.Z., M.F.B., J.J.-B., M.I.C.); Department of Geriatric Medicine, Kyoto University Hospital, Kyoto, Japan (M.I.); Case Cardiovascular Research Institute, Department of Medicine, Case Western Reserve University School of Medicine, Cleveland, OH (S.M.H.); and Department of Pathology, Children's Hospital and Harvard Medical School, Boston, MA (T.C.).
Vannessa M DavisFrom the Vascular Research Division, Department of Pathology, Center for Excellence in Vascular Biology (D.S.M., P.O.D., V.M.D., T.C.) and Cardiovascular Division (J.P., J.D.B.), Brigham and Women's Hospital and Harvard Medical School, Boston, MA; Advanced Diagnostics Division, Toronto General Research Institute, University Health Network Toronto, Ontario, Canada (M.I., M.C., A.S., A.C.L., S.-N.Z., M.F.B., J.J.-B., M.I.C.); Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada (M.I., M.C., A.S., A.C.L., S.-N.Z., M.F.B., J.J.-B., M.I.C.); Department of Geriatric Medicine, Kyoto University Hospital, Kyoto, Japan (M.I.); Case Cardiovascular Research Institute, Department of Medicine, Case Western Reserve University School of Medicine, Cleveland, OH (S.M.H.); and Department of Pathology, Children's Hospital and Harvard Medical School, Boston, MA (T.C.).
Jorge PlutzkyFrom the Vascular Research Division, Department of Pathology, Center for Excellence in Vascular Biology (D.S.M., P.O.D., V.M.D., T.C.) and Cardiovascular Division (J.P., J.D.B.), Brigham and Women's Hospital and Harvard Medical School, Boston, MA; Advanced Diagnostics Division, Toronto General Research Institute, University Health Network Toronto, Ontario, Canada (M.I., M.C., A.S., A.C.L., S.-N.Z., M.F.B., J.J.-B., M.I.C.); Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada (M.I., M.C., A.S., A.C.L., S.-N.Z., M.F.B., J.J.-B., M.I.C.); Department of Geriatric Medicine, Kyoto University Hospital, Kyoto, Japan (M.I.); Case Cardiovascular Research Institute, Department of Medicine, Case Western Reserve University School of Medicine, Cleveland, OH (S.M.H.); and Department of Pathology, Children's Hospital and Harvard Medical School, Boston, MA (T.C.).
Jonathan D BrownFrom the Vascular Research Division, Department of Pathology, Center for Excellence in Vascular Biology (D.S.M., P.O.D., V.M.D., T.C.) and Cardiovascular Division (J.P., J.D.B.), Brigham and Women's Hospital and Harvard Medical School, Boston, MA; Advanced Diagnostics Division, Toronto General Research Institute, University Health Network Toronto, Ontario, Canada (M.I., M.C., A.S., A.C.L., S.-N.Z., M.F.B., J.J.-B., M.I.C.); Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada (M.I., M.C., A.S., A.C.L., S.-N.Z., M.F.B., J.J.-B., M.I.C.); Department of Geriatric Medicine, Kyoto University Hospital, Kyoto, Japan (M.I.); Case Cardiovascular Research Institute, Department of Medicine, Case Western Reserve University School of Medicine, Cleveland, OH (S.M.H.); and Department of Pathology, Children's Hospital and Harvard Medical School, Boston, MA (T.C.).
Saptarsi M HaldarFrom the Vascular Research Division, Department of Pathology, Center for Excellence in Vascular Biology (D.S.M., P.O.D., V.M.D., T.C.) and Cardiovascular Division (J.P., J.D.B.), Brigham and Women's Hospital and Harvard Medical School, Boston, MA; Advanced Diagnostics Division, Toronto General Research Institute, University Health Network Toronto, Ontario, Canada (M.I., M.C., A.S., A.C.L., S.-N.Z., M.F.B., J.J.-B., M.I.C.); Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada (M.I., M.C., A.S., A.C.L., S.-N.Z., M.F.B., J.J.-B., M.I.C.); Department of Geriatric Medicine, Kyoto University Hospital, Kyoto, Japan (M.I.); Case Cardiovascular Research Institute, Department of Medicine, Case Western Reserve University School of Medicine, Cleveland, OH (S.M.H.); and Department of Pathology, Children's Hospital and Harvard Medical School, Boston, MA (T.C.).
Allan SiuFrom the Vascular Research Division, Department of Pathology, Center for Excellence in Vascular Biology (D.S.M., P.O.D., V.M.D., T.C.) and Cardiovascular Division (J.P., J.D.B.), Brigham and Women's Hospital and Harvard Medical School, Boston, MA; Advanced Diagnostics Division, Toronto General Research Institute, University Health Network Toronto, Ontario, Canada (M.I., M.C., A.S., A.C.L., S.-N.Z., M.F.B., J.J.-B., M.I.C.); Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada (M.I., M.C., A.S., A.C.L., S.-N.Z., M.F.B., J.J.-B., M.I.C.); Department of Geriatric Medicine, Kyoto University Hospital, Kyoto, Japan (M.I.); Case Cardiovascular Research Institute, Department of Medicine, Case Western Reserve University School of Medicine, Cleveland, OH (S.M.H.); and Department of Pathology, Children's Hospital and Harvard Medical School, Boston, MA (T.C.).
Andrew C LauFrom the Vascular Research Division, Department of Pathology, Center for Excellence in Vascular Biology (D.S.M., P.O.D., V.M.D., T.C.) and Cardiovascular Division (J.P., J.D.B.), Brigham and Women's Hospital and Harvard Medical School, Boston, MA; Advanced Diagnostics Division, Toronto General Research Institute, University Health Network Toronto, Ontario, Canada (M.I., M.C., A.S., A.C.L., S.-N.Z., M.F.B., J.J.-B., M.I.C.); Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada (M.I., M.C., A.S., A.C.L., S.-N.Z., M.F.B., J.J.-B., M.I.C.); Department of Geriatric Medicine, Kyoto University Hospital, Kyoto, Japan (M.I.); Case Cardiovascular Research Institute, Department of Medicine, Case Western Reserve University School of Medicine, Cleveland, OH (S.M.H.); and Department of Pathology, Children's Hospital and Harvard Medical School, Boston, MA (T.C.).
Su-Ning ZhuFrom the Vascular Research Division, Department of Pathology, Center for Excellence in Vascular Biology (D.S.M., P.O.D., V.M.D., T.C.) and Cardiovascular Division (J.P., J.D.B.), Brigham and Women's Hospital and Harvard Medical School, Boston, MA; Advanced Diagnostics Division, Toronto General Research Institute, University Health Network Toronto, Ontario, Canada (M.I., M.C., A.S., A.C.L., S.-N.Z., M.F.B., J.J.-B., M.I.C.); Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada (M.I., M.C., A.S., A.C.L., S.-N.Z., M.F.B., J.J.-B., M.I.C.); Department of Geriatric Medicine, Kyoto University Hospital, Kyoto, Japan (M.I.); Case Cardiovascular Research Institute, Department of Medicine, Case Western Reserve University School of Medicine, Cleveland, OH (S.M.H.); and Department of Pathology, Children's Hospital and Harvard Medical School, Boston, MA (T.C.).
Mayada F BasheerFrom the Vascular Research Division, Department of Pathology, Center for Excellence in Vascular Biology (D.S.M., P.O.D., V.M.D., T.C.) and Cardiovascular Division (J.P., J.D.B.), Brigham and Women's Hospital and Harvard Medical School, Boston, MA; Advanced Diagnostics Division, Toronto General Research Institute, University Health Network Toronto, Ontario, Canada (M.I., M.C., A.S., A.C.L., S.-N.Z., M.F.B., J.J.-B., M.I.C.); Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada (M.I., M.C., A.S., A.C.L., S.-N.Z., M.F.B., J.J.-B., M.I.C.); Department of Geriatric Medicine, Kyoto University Hospital, Kyoto, Japan (M.I.); Case Cardiovascular Research Institute, Department of Medicine, Case Western Reserve University School of Medicine, Cleveland, OH (S.M.H.); and Department of Pathology, Children's Hospital and Harvard Medical School, Boston, MA (T.C.).
Tucker CollinsFrom the Vascular Research Division, Department of Pathology, Center for Excellence in Vascular Biology (D.S.M., P.O.D., V.M.D., T.C.) and Cardiovascular Division (J.P., J.D.B.), Brigham and Women's Hospital and Harvard Medical School, Boston, MA; Advanced Diagnostics Division, Toronto General Research Institute, University Health Network Toronto, Ontario, Canada (M.I., M.C., A.S., A.C.L., S.-N.Z., M.F.B., J.J.-B., M.I.C.); Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada (M.I., M.C., A.S., A.C.L., S.-N.Z., M.F.B., J.J.-B., M.I.C.); Department of Geriatric Medicine, Kyoto University Hospital, Kyoto, Japan (M.I.); Case Cardiovascular Research Institute, Department of Medicine, Case Western Reserve University School of Medicine, Cleveland, OH (S.M.H.); and Department of Pathology, Children's Hospital and Harvard Medical School, Boston, MA (T.C.).
Jenny Jongstra-BilenFrom the Vascular Research Division, Department of Pathology, Center for Excellence in Vascular Biology (D.S.M., P.O.D., V.M.D., T.C.) and Cardiovascular Division (J.P., J.D.B.), Brigham and Women's Hospital and Harvard Medical School, Boston, MA; Advanced Diagnostics Division, Toronto General Research Institute, University Health Network Toronto, Ontario, Canada (M.I., M.C., A.S., A.C.L., S.-N.Z., M.F.B., J.J.-B., M.I.C.); Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada (M.I., M.C., A.S., A.C.L., S.-N.Z., M.F.B., J.J.-B., M.I.C.); Department of Geriatric Medicine, Kyoto University Hospital, Kyoto, Japan (M.I.); Case Cardiovascular Research Institute, Department of Medicine, Case Western Reserve University School of Medicine, Cleveland, OH (S.M.H.); and Department of Pathology, Children's Hospital and Harvard Medical School, Boston, MA (T.C.).
Myron I CybulskyFrom the Vascular Research Division, Department of Pathology, Center for Excellence in Vascular Biology (D.S.M., P.O.D., V.M.D., T.C.) and Cardiovascular Division (J.P., J.D.B.), Brigham and Women's Hospital and Harvard Medical School, Boston, MA; Advanced Diagnostics Division, Toronto General Research Institute, University Health Network Toronto, Ontario, Canada (M.I., M.C., A.S., A.C.L., S.-N.Z., M.F.B., J.J.-B., M.I.C.); Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada (M.I., M.C., A.S., A.C.L., S.-N.Z., M.F.B., J.J.-B., M.I.C.); Department of Geriatric Medicine, Kyoto University Hospital, Kyoto, Japan (M.I.); Case Cardiovascular Research Institute, Department of Medicine, Case Western Reserve University School of Medicine, Cleveland, OH (S.M.H.); and Department of Pathology, Children's Hospital and Harvard Medical School, Boston, MA (T.C.). myron.cybulsky@utoronto.ca milstone@rascal.med.harvard.edu.
Kyoto University Hospital · JPUniversity of Toronto · CACase Western Reserve University · USUniversity Health Network · CAUniversity School · US
Funding
VCAM-1 IN CHRONIC INFLAMMATORY AND IMMUNE PROCESSESP01HL036028 · NHLBI · BRIGHAM AND WOMEN'S HOSPITAL · PI LUSCINSKAS, FRANCIS W. · 1985 to 2013
$32.1MTissue AnalysesP01HL048743 · NHLBI · BRIGHAM AND WOMEN'S HOSPITAL · PI GLADYSHEV, VADIM N. · 1992 to 2014
$26.3MRegulation of Chromatin Signaling in Heart Failure by the BRD4 Bromodomain Protein.R01HL127240 · NHLBI · UNIVERSITY OF COLORADO DENVER · PI MCKINSEY, TIMOTHY, SRIVASTAVA, DEEPAK · 2015 to 2022
$6.4MKLF15 and Transcriptional Control of Muscle MetabolismR01DK093821 · NIDDK · J. DAVID GLADSTONE INSTITUTES · PI HALDAR, SAPTARSI · 2013 to 2017
$1.8MPPARg in trophoblast and placental developmentR01HD040895 · NICHD · BRIGHAM AND WOMEN'S HOSPITAL · PI MILSTONE, DAVID S · 2003 to 2007
$1.5MHepatic Lipase, PPAR-delta and Fatty Acid MetabolismK08HL105678 · NHLBI · VANDERBILT UNIVERSITY MEDICAL CENTER · PI BROWN, JONATHAN DAVID · 2011 to 2015
$678kIL-2 Family Cytokines and their Receptors--Biology of the IL-7/TSLP SystemsZ01HL005409 · NHLBI · NATIONAL HEART, LUNG, AND BLOOD INSTITUTE · PI LEONARD, WARREN J · 2008 to 2008
$668kCIHR MOP-106522Intramural NIH HHS Z01 HL005409NHLBI NIH HHS K08 HL105678NHLBI NIH HHS P01 HL036028NHLBI NIH HHS P01 HL048743NHLBI NIH HHS P01 HL30628NHLBI NIH HHS P01 HL48743NHLBI NIH HHS R01 HL127240NHLBI NIH HHS R29-HL5409-5NICHD NIH HHS R01 HD040895NIDDK NIH HHS R01 DK093821
Abstract
rationaleHuman and murine Vcam1 promoters contain 2 adjacent nuclear factor-κB (NF-κB)-binding elements. Both are essential for cytokine-induced transcription of transiently transfected promoter-reporter constructs. However, the relevance of these insights to regulation of the endogenous Vcam1 gene and to pathophysiological processes in vivo remained unknown.
objectiveDetermine the role of the 5' NF-κB-binding element in expression of the endogenous Vcam1 gene. METHODS AND
resultsHomologous recombination in embryonic stem cells was used to inactivate the 5' NF-κB element in the Vcam1 promoter and alter 3 nucleotides in the 5' untranslated region to allow direct comparison of wild-type versus mutant allele RNA expression and chromatin configuration in heterozygous mice. Systemic treatment with inflammatory cytokines or endotoxin (lipopolysaccharide) induced lower expression of the mutant allele relative to wild-type by endothelial cells in the aorta, heart, and lungs. The mutant allele also showed lower endothelial expression in 2-week atherosclerotic lesions in Vcam1 heterozygous/low-density lipoprotein receptor-deficient mice fed a cholesterol-rich diet. In vivo chromatin immunoprecipitation assays of heart showed diminished lipopolysaccharide-induced association of RNA polymerase 2 and NF-κB p65 with the mutant promoter. In contrast, expression of mutant and wild-type alleles was comparable in intimal cells of wire-injured carotid artery and 4- to 12-week atherosclerotic lesions.
conclusionsThis study highlights differences between in vivo and in vitro promoter analyses, and reveals a differential role for a NF-κB transcriptional response element in endothelial vascular cell adhesion molecule-1 expression induced by inflammatory cytokines or a cholesterol-rich diet versus intimal cell expression in atherosclerotic lesions and injured arteries.
Indexed as
5' Untranslated RegionsAnimalsAtherosclerosisCarotid Artery InjuriesCells, CulturedChemotaxis, LeukocyteCholesterol, DietaryEndothelial CellsEndothelium, VascularE-SelectinHumansMiceMice, Inbred C57BLMice, KnockoutPromoter Regions, GeneticProtein Interaction Mapping5' Untranslated RegionsCholesterol, DietaryE-SelectinReceptors, LDLRela protein, mouseRNA Polymerase IITranscription Factor RelAVascular Cell Adhesion Molecule-1atherosclerosischromatin immunoprecipitationendothelial cellsgene expressionNF-κBtunica intimavascular cell adhesion molecule-1
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