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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, 114(13), E2766-E2775. National Academy of Sciences
- 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-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.
- Subjects :
- 0301 basic medicine
Male
NF-KAPPA-B
ATTENUATES ATHEROSCLEROSIS
COP9 signalosome
Mice
JAB1 INTERACTS
NEDDylation
Aorta
GENE-EXPRESSION
Mice, Knockout
Multidisciplinary
NF-kappa B
Cullin Proteins
Cell biology
medicine.anatomical_structure
PNAS Plus
Atherosclerosi
Female
medicine.symptom
Endothelium
NEDD8 Protein
MLN4924
Inflammation
ACUTE MYELOID-LEUKEMIA
Biology
Proinflammatory cytokine
03 medical and health sciences
Apolipoproteins E
In vivo
medicine
Animals
Humans
E-DEFICIENT MICE
COP9 Signalosome Complex
Monocyte
Macrophages
Endothelial Cells
EXPERIMENTAL ATHEROSCLEROSIS
Atherosclerosis
Hypoxia-Inducible Factor 1, alpha Subunit
Mice, Inbred C57BL
030104 developmental biology
inflammation
Immunology
ENDOTHELIAL DYSFUNCTION
MODULATE AP-1 ACTIVITY
Neddylation
NEDD8-ACTIVATING ENZYME-INHIBITOR
Peptide Hydrolases
Subjects
Details
- Language :
- English
- ISSN :
- 00278424
- Volume :
- 114
- Issue :
- 13
- Database :
- OpenAIRE
- Journal :
- Proceedings of the National Academy of Sciences of the United States of America
- Accession number :
- edsair.doi.dedup.....1f36641b6abaf48b9ec38dfda828de60