Inhibition of atherogenesis by the COP9 signalosome subunit 5 in vivo

Yaw Asare, Miriam Ommer, Florence. A. Azombo, Setareh Alampour-Rajabi, Marieke Sternkopf, Maryam Sanati, Marion J. Gijbels, Corinna Schmitz, Dzmitry Sinitski, Pathricia V. Tilstam, Hongqi Lue, Andre Gessner, Denise Lange, Johannes A. Schmid, Christian Weber, Martin Dichgans, Joachim Jankowski, Ruggero Pardi, Menno P. J. de Winther, Heidi Noels*Juergen Bernhagen*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

26 Citations (Web of Science)

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.

Original languageEnglish
Pages (from-to)E2766-E2775
Number of pages10
JournalProceedings of the National Academy of Sciences of the United States of America
Volume114
Issue number13
DOIs
Publication statusPublished - 14 Mar 2017

Keywords

  • COP9 signalosome
  • atherosclerosis
  • inflammation
  • NEDDylation
  • MLN4924
  • 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

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