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Regulation of vascular smooth muscle cell proliferation. Role of NF-kappaB revisited

Item Type:Article
Title:Regulation of vascular smooth muscle cell proliferation. Role of NF-kappaB revisited
Creators Name:Mehrhof, F.B. and Schmidt-Ullrich, R. and Dietz, R. and Scheidereit, C.
Abstract:The transcription factor NF-κB regulates cell cycle progression and proliferation in a number of cell types. An important unresolved issue is the potential role of NF-κB in the proliferation of vascular smooth muscle cells (VSMCs) as a basis for the development of vascular disease. To investigate the contribution of NF-κB to mitogen-induced proliferation of VSMCs, a knock-in mouse model expressing the NF-κB superrepressor IκB{alpha}ΔN (cIκB{alpha}{delta}N) was used. Comparing wild-type and IκB{alpha}{delta}N-expressing VSMCs, we found that proliferation rates did not differ after mitogenic stimulation by platelet-derived growth-factor-BB (PDGF-BB) or serum. In line with this, NF-κB activation was not observed in VSMCs derived from transgenic mice expressing an NF-κB-dependent lacZ reporter (c(Igk)3conalacZ). We further show, that classical mitogenic signaling pathways (namely mitogen-activated protein kinase [MAPK] and the phosphatidyl-inositol-3-OH- kinase [PI3K] pathways) control VSMC proliferation, but independently of NF-κB activation. In contrast to VSMCs, mouse embryonic fibroblasts (MEFs) derived from IκB{alpha}{delta}N-expressing mice showed significantly impaired proliferation rates after mitogenic stimulation. This was reflected by strongly impaired cyclin D1 expression in serum-stimulated MEFs derived from (cIκB{alpha}{delta}N) mice. These results implicate that essential pathogenetic functions of NF-κB in the development of atherosclerosis involve apoptotic and inflammatory signaling of VSMCs rather than proliferation. They further provide genetic evidence for a cell-type restricted requirement of NF-κB in the control of cellular proliferation.
Keywords:Atherosclerosis, MAPK, NF-κB, PI3K, VSMC proliferation, Animals, Mice
Source:Circulation Research
Publisher:American Heart Association
Page Range:958-964
Date:1 January 2005
Official Publication:https://doi.org/10.1161/01.RES.0000166924.31219.49
PubMed:View item in PubMed

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