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Inhibition of atherogenesis by the COP9 signalosome subunit 5 in vivo.
- Source :
-
Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2017 Mar 28; Vol. 114 (13), pp. E2766-E2775. Date of Electronic Publication: 2017 Mar 14. - Publication Year :
- 2017
-
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-specific Csn5 deletion. Genetic deletion of Csn5 in Apoe <superscript>- / -</superscript> 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-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 marker Arginase 1 in 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.
- Subjects :
- Animals
Aorta metabolism
Apolipoproteins E genetics
Apolipoproteins E metabolism
Atherosclerosis genetics
Atherosclerosis metabolism
COP9 Signalosome Complex genetics
Cullin Proteins genetics
Cullin Proteins metabolism
Endothelial Cells enzymology
Endothelial Cells metabolism
Female
Humans
Hypoxia-Inducible Factor 1, alpha Subunit genetics
Hypoxia-Inducible Factor 1, alpha Subunit metabolism
Macrophages enzymology
Macrophages metabolism
Male
Mice
Mice, Inbred C57BL
Mice, Knockout
NEDD8 Protein genetics
NEDD8 Protein metabolism
NF-kappa B genetics
NF-kappa B metabolism
Peptide Hydrolases genetics
Atherosclerosis enzymology
COP9 Signalosome Complex metabolism
Peptide Hydrolases metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1091-6490
- Volume :
- 114
- Issue :
- 13
- Database :
- MEDLINE
- Journal :
- Proceedings of the National Academy of Sciences of the United States of America
- Publication Type :
- Academic Journal
- Accession number :
- 28292897
- Full Text :
- https://doi.org/10.1073/pnas.1618411114