title: Inhibition of atherogenesis by the COP9 signalosome subunit 5 in vivo.
abstract: Constitutive photomorphogenesis 9 (COP9) signalosome 5 (CSN5), an isopeptidase that removes neural precursor cell-expressed, developmentally down-regulated 8 (NEDD8) moieties from cullins (thus termed "deNEDDylase") and a subunit of the cullin-RING E3 ligase-regulating COP9 signalosome complex, attenuates proinflammatory NF-κB signaling. We previously showed that CSN5 is up-regulated in human atherosclerotic arteries. Here, we investigated the role of CSN5 in atherogenesis in vivo by using mice with myeloid-specificCsn5deletion. Genetic deletion ofCsn5inApoe-/-mice markedly exacerbated atherosclerotic lesion formation. This was broadly observed in aortic root, arch, and total aorta of male mice, whereas the effect was less pronounced and site-specific in females. Mechanistically,Csn5KO potentiated NF-κB signaling and proinflammatory cytokine expression in macrophages, whereas HIF-1α levels were reduced. Inversely, inhibition of NEDDylation by MLN4924 blocked proinflammatory gene expression and NF-κB activation while enhancing HIF-1α levels and the expression of M2 markerArginase 1in inflammatory-elicited macrophages. MLN4924 further attenuated the expression of chemokines and adhesion molecules in endothelial cells and reduced NF-κB activation and monocyte arrest on activated endothelium in vitro. In vivo, MLN4924 reduced LPS-induced inflammation, favored an antiinflammatory macrophage phenotype, and decreased the progression of early atherosclerotic lesions in mice. On the contrary, MLN4924 treatment increased neutrophil and monocyte counts in blood and had no net effect on the progression of more advanced lesions. Our data show that CSN5 is atheroprotective. We conclude that MLN4924 may be useful in preventing early atherogenesis, whereas selectively promoting CSN5-mediated deNEDDylation may be beneficial in all stages of atherosclerosis.
authors.affiliation: Institute for Stroke and Dementia Research, Klinikum der Universität München, Ludwig-Maximilians-University, 81377 Munich, Germany.|Institute for Molecular Cardiovascular Research, Rheinisch-Westfälische Technische Hochschule Aachen University, 52074 Aachen, Germany.|Institute of Biochemistry and Molecular Cell Biology, Rheinisch-Westfälische Technische Hochschule Aachen University, 52074 Aachen, Germany.
authors.forename: Yaw
authors.initials: Y
authors.lastname: Asare
authors.affiliation: Institute for Stroke and Dementia Research, Klinikum der Universität München, Ludwig-Maximilians-University, 81377 Munich, Germany.
authors.forename: Miriam
authors.initials: M
authors.lastname: Ommer
authors.affiliation: Institute of Biochemistry and Molecular Cell Biology, Rheinisch-Westfälische Technische Hochschule Aachen University, 52074 Aachen, Germany.
authors.forename: Florence A
authors.initials: FA
authors.lastname: Azombo
authors.affiliation: Institute for Molecular Cardiovascular Research, Rheinisch-Westfälische Technische Hochschule Aachen University, 52074 Aachen, Germany.
authors.forename: Setareh
authors.initials: S
authors.lastname: Alampour-Rajabi
authors.affiliation: Institute for Molecular Cardiovascular Research, Rheinisch-Westfälische Technische Hochschule Aachen University, 52074 Aachen, Germany.
authors.forename: Marieke
authors.initials: M
authors.lastname: Sternkopf
authors.affiliation: Institute for Molecular Cardiovascular Research, Rheinisch-Westfälische Technische Hochschule Aachen University, 52074 Aachen, Germany.
authors.forename: Maryam
authors.initials: M
authors.lastname: Sanati
authors.affiliation: Cardiovascular Research Institute Maastricht, Maastricht University, 6229 Maastricht, The Netherlands.|Department of Medical Biochemistry, Academic Medical Center, University of Amsterdam, 1105AZ Amsterdam, The Netherlands.
authors.forename: Marion J
authors.initials: MJ
authors.lastname: Gijbels
authors.affiliation: Institute for Stroke and Dementia Research, Klinikum der Universität München, Ludwig-Maximilians-University, 81377 Munich, Germany.
authors.forename: Corinna
authors.initials: C
authors.lastname: Schmitz
authors.affiliation: Institute for Stroke and Dementia Research, Klinikum der Universität München, Ludwig-Maximilians-University, 81377 Munich, Germany.
authors.forename: Dzmitry
authors.initials: D
authors.lastname: Sinitski
authors.affiliation: Institute for Molecular Cardiovascular Research, Rheinisch-Westfälische Technische Hochschule Aachen University, 52074 Aachen, Germany.
authors.forename: Pathricia V
authors.initials: PV
authors.lastname: Tilstam
authors.affiliation: Institute of Biochemistry and Molecular Cell Biology, Rheinisch-Westfälische Technische Hochschule Aachen University, 52074 Aachen, Germany.
authors.forename: Hongqi
authors.initials: H
authors.lastname: Lue
authors.affiliation: Institute of Clinical Microbiology and Hygiene, University Hospital of Regensburg, 93053 Regensburg, Germany.
authors.forename: André
authors.initials: A
authors.lastname: Gessner
authors.affiliation: Institute for Molecular Cardiovascular Research, Rheinisch-Westfälische Technische Hochschule Aachen University, 52074 Aachen, Germany.
authors.forename: Denise
authors.initials: D
authors.lastname: Lange
authors.affiliation: Center for Physiology and Pharmacology, Department of Vascular Biology and Thrombosis Research, Medical University Vienna, 1090 Vienna, Austria.
authors.forename: Johannes A
authors.initials: JA
authors.lastname: Schmid
authors.affiliation: Cardiovascular Research Institute Maastricht, Maastricht University, 6229 Maastricht, The Netherlands.|Institute for Cardiovascular Prevention, Ludwig-Maximilians-University Munich, 80336 Munich, Germany.|Munich Heart Alliance, 80802 Munich, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Weber
authors.affiliation: Institute for Stroke and Dementia Research, Klinikum der Universität München, Ludwig-Maximilians-University, 81377 Munich, Germany.|Munich Cluster for Systems Neurology, 81377 Munich, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Dichgans
authors.affiliation: Institute for Molecular Cardiovascular Research, Rheinisch-Westfälische Technische Hochschule Aachen University, 52074 Aachen, Germany.
authors.forename: Joachim
authors.initials: J
authors.lastname: Jankowski
authors.affiliation: School of Medicine and Scientific Institute, Vita-Salute San Raffaele University, 20123 Milan, Italy.
authors.forename: Ruggero
authors.initials: R
authors.lastname: Pardi
authors.affiliation: Department of Medical Biochemistry, Academic Medical Center, University of Amsterdam, 1105AZ Amsterdam, The Netherlands.|Institute for Cardiovascular Prevention, Ludwig-Maximilians-University Munich, 80336 Munich, Germany.
authors.forename: Menno P J
authors.initials: MP
authors.lastname: de Winther
authors.affiliation: Institute for Molecular Cardiovascular Research, Rheinisch-Westfälische Technische Hochschule Aachen University, 52074 Aachen, Germany; hnoels@ukaachen.de juergen.bernhagen@med.uni-muenchen.de.
authors.forename: Heidi
authors.initials: H
authors.lastname: Noels
authors.affiliation: Institute for Stroke and Dementia Research, Klinikum der Universität München, Ludwig-Maximilians-University, 81377 Munich, Germany; hnoels@ukaachen.de juergen.bernhagen@med.uni-muenchen.de.|Institute of Biochemistry and Molecular Cell Biology, Rheinisch-Westfälische Technische Hochschule Aachen University, 52074 Aachen, Germany.|Munich Heart Alliance, 80802 Munich, Germany.|Munich Cluster for Systems Neurology, 81377 Munich, Germany.
authors.forename: Jürgen
authors.initials: J
authors.lastname: Bernhagen
mesh_terms: D000818:Animals; D001011:Aorta / Q000378:metabolism; D001057:Apolipoproteins E / Q000235:genetics / Q000378:metabolism; D050197:Atherosclerosis / Q000201:enzymology* / Q000235:genetics / Q000378:metabolism; D000075686:COP9 Signalosome Complex / Q000235:genetics / Q000378:metabolism*; D044842:Cullin Proteins / Q000235:genetics / Q000378:metabolism; D042783:Endothelial Cells / Q000201:enzymology / Q000378:metabolism; D005260:Female; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism; D008264:Macrophages / Q000201:enzymology / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D000075687:NEDD8 Protein / Q000235:genetics / Q000378:metabolism; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D010447:Peptide Hydrolases / Q000235:genetics / Q000378:metabolism*
chemical_list: D001057:Apolipoproteins E; D044842:Cullin Proteins; C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D000075687:NEDD8 Protein; D016328:NF-kappa B; D010447:Peptide Hydrolases; C501490:Cops5 protein, mouse; D000075686:COP9 Signalosome Complex
keywords: COP9 signalosome; MLN4924; NEDDylation; atherosclerosis; inflammation