Universität zu Köln

Imai, Takashi, Pasparakis, Manolis ORCID: 0000-0002-9870-0966 and Polykratis, Apostolos (2022). Smooth muscle cell specific NEMO deficiency inhibits atherosclerosis in ApoE(-/-) mice. Sci Rep, 12 (1). BERLIN: NATURE PORTFOLIO. ISSN 2045-2322

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Abstract

The development of atherosclerotic plaques is the result of a chronic inflammatory response coordinated by stromal and immune cellular components of the vascular wall. While endothelial cells and leukocytes are well-recognised mediators of inflammation in atherosclerosis, the role of smooth muscle cells (SMCs) remains incompletely understood. Here we aimed to address the role of canonical NF-kappa B signalling in SMCs in the development of atherosclerosis. We investigated the role of NF-kappa B signalling in SMCs in atherosclerosis by employing SMC-specific ablation of NEMO, an IKK complex subunit that is essential for canonical NF-kappa B activation, in ApoE(-/-) mice. We show that SMC-specific ablation of NEMO (NEMOSMCiKO) inhibited high fat diet induced atherosclerosis in ApoE(-/-) mice. NEMOSMCiKO/ApoE(-/-) mice developed less and smaller atherosclerotic plaques, which contained fewer macrophages, decreased numbers of apoptotic cells and smaller necrotic areas and showed reduced inflammation compared to the plaques of ApoE(-/-) mice. In addition, the plaques of NEMOSMCiKO/ApoE(-/-) mice showed higher expression of alpha-SMA and lower expression of the transcriptional factor KLF4 compared to those of ApoE(-/-) mice. Consistently, in vitro, NEMO-deficient SMCs exhibited reduced proliferation and migration, as well as decreased KLF4 expression and lower production of IL-6 and MCP-1 upon inflammatory stimulus (TNF or LPS) compared to NEMO-expressing SMCs. In conclusion, NEMO-dependent activation of NF-kappa B signalling in SMCs critically contributes to the pathogenesis of atherosclerosis by regulating SMC proliferation, migration and phenotype switching in response to inflammatory stimuli.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Imai, Takashi UNSPECIFIED UNSPECIFIED UNSPECIFIED Pasparakis, Manolis UNSPECIFIED orcid.org/0000-0002-9870-0966 UNSPECIFIED Polykratis, Apostolos UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-661351
DOI:	10.1038/s41598-022-16737-8
Journal or Publication Title:	Sci Rep
Volume:	12
Number:	1
Date:	2022
Publisher:	NATURE PORTFOLIO
Place of Publication:	BERLIN
ISSN:	2045-2322
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language NF-KAPPA-B; LDL RECEPTOR-DEFICIENT; UP-REGULATION; ACTIVATION; INFLAMMATION; LESIONS; GROWTH; HYPERCHOLESTEROLEMIA; PROLIFERATION; INCREASES Multiple languages Multidisciplinary Sciences Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/66135