Inflammatory processes mark all stages of atherogenesis. One of the key regulators of inflammation is the transcription factor nuclear factor kappa B (Nf-kb). Nf-kb is the general name for a whole family of dimeric transcription factors. One can distinguish between a classical and an alternative pathway with Rela/p50 (Nf-kb1) and Relb/p52 (Nf-kb2) representing the terminal transcription factors, respectively. Classical Nf-kb1 signaling has been associated with atherosclerotic lesion development many times, mainly because of its regulation of many pro-inflammatory proteins with an established role in atherogenesis. Recent studies provided evidence of crosstalk between classical Nf-kb1 and alternative Nf-kb2 signaling, implicating a potential role for Nf-kb2 in atherogenesis. The aim of the present study was to investigate the influence of Nf-kb2 on atherosclerotic lesion development in a knockout mouse model.
Nfkb2 knockout (Nfkb2-/-) mice were generated on two different atherosclerosis sensible backgrounds, the Apoe- and Ldlr- deficient background. Quantification of atherosclerotic lesion development showed, that Nfkb2-/- mice developed significantly more atherosclerosis at the brachiocephalic artery than wild type controls, indicating a protective effect of Nf-kb2 on atherogenesis. Further expression analyses in bone marrow-derived macrophages (BMDM) revealed highly significant upregulation of matrix metalloproteinase 9 (Mmp9) in Nfkb2-/- mice. Overexpression of Mmp9 was associated with enhanced macrophage migration across extracellular matrix in vitro and an inflammatory plaque phenotype with advanced, macrophage-rich lesions. Accordingly, increased Mmp9 expression in Nfkb2-/- macrophages might have contributed to enhanced lesion development in these mice.
| Identifer | oai:union.ndltd.org:DRESDEN/oai:qucosa.de:bsz:15-qucosa-149753 |
| Date | 30 July 2014 |
| Creators | Dühring, Sarah |
| Contributors | Universität Leipzig, Medizinische Fakultät, Prof. Dr. med. Joachim Thiery, Prof. Dr. med. Daniel Teupser, Prof. Dr. med. Dr. rer. nat. Lesca M. Holdt, Prof. Dr. med. Michael Stumvoll, Prof. Dr. med. Gerhard Schuler |
| Publisher | Universitätsbibliothek Leipzig |
| Source Sets | Hochschulschriftenserver (HSSS) der SLUB Dresden |
| Language | English |
| Detected Language | English |
| Type | doc-type:doctoralThesis |
| Format | application/pdf |
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