Year: 2014
Type: dissertation
Abstract: 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.
Author: S Dühring
Language: English
Subfield: Immunology
Field: Immunology and Microbiology
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W1812032761