Asare, Yaw and Ommer, Miriam and Azombo, Florence. A. and Alampour-Rajabi, Setareh and Sternkopf, Marieke and Sanati, Maryam and Gijbels, Marion J. and Schmitz, Corinna and Sinitski, Dzmitry and Tilstam, Pathricia V. and Lue, Hongqi and Gessner, Andre and Lange, Denise and Schmid, Johannes A. and Weber, Christian and Dichgans, Martin and Jankowski, Joachim and Pardi, Ruggero and de Winther, Menno P. J. and Noels, Heidi and Bernhagen, Juergen (2017) Inhibition of atherogenesis by the COP9 signalosome subunit 5 in vivo. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 114 (13). E2766-E2775. ISSN 0027-8424,
Full text not available from this repository. (Request a copy)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-kappa B 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-specific Csn5 deletion. Genetic deletion of Csn5 in Apoe(-/-) 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, Csn5 KO potentiated NF-kappa B signaling and proinflammatory cytokine expression in macrophages, whereas HIF-1 alpha levels were reduced. Inversely, inhibition of NEDDylation by MLN4924 blocked proinflammatory gene expression and NF-kappa B activation while enhancing HIF-1 alpha levels and the expression of M2 marker Arginase 1 in inflammatory-elicited macrophages. MLN4924 further attenuated the expression of chemokines and adhesion molecules in endothelial cells and reduced NF-kappa B 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.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | NF-KAPPA-B; NEDD8-ACTIVATING ENZYME-INHIBITOR; E-DEFICIENT MICE; ACUTE MYELOID-LEUKEMIA; MODULATE AP-1 ACTIVITY; EXPERIMENTAL ATHEROSCLEROSIS; ATTENUATES ATHEROSCLEROSIS; ENDOTHELIAL DYSFUNCTION; GENE-EXPRESSION; JAB1 INTERACTS; COP9 signalosome; atherosclerosis; inflammation; NEDDylation; MLN4924 |
| Subjects: | 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Lehrstuhl für Medizinische Mikrobiologie und Hygiene |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 14 Dec 2018 13:00 |
| Last Modified: | 25 Feb 2019 12:22 |
| URI: | https://pred.uni-regensburg.de/id/eprint/197 |
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