The NF-κB signal transduction pathway in aortic endothelial cells is primed for activation in regions predisposed to atherosclerotic lesion formation

Abstract

Atherosclerotic lesions form at distinct sites in the arterial tree, suggesting that hemodynamic forces influence the initiation of atherogenesis. If NF-B plays a role in atherogenesis, then the activation of this signal transduction pathway in arterial endothelium should show topographic variation. The expression of NF-B͞ IB components and NF-B activation was evaluated by specific antibody staining, en face confocal microscopy, and image analysis of endothelium in regions of mouse proximal aorta with high and low probability (HP and LP) for atherosclerotic lesion development. In control C57BL͞6 mice, expression levels of p65, IB␣, and IB␤ were 5-to 18-fold higher in the HP region, yet NF-B was activated in a minority of endothelial cells. This suggested that NF-B signal transduction was primed for activation in HP regions on encountering an activation stimulus. Lipopolysaccharide treatment or feeding low-density lipoprotein receptor knockout mice an atherogenic diet resulted in NF-B activation and up-regulated expression of NF-B-inducible genes predominantly in HP region endothelium. Preferential regional activation of endothelial NF-B by systemic stimuli, including hypercholesterolemia, may contribute to the localization of atherosclerotic lesions at sites with high steadystate expression levels of NF-B͞IB components.atherosclerosis ͉ p65 ͉ IB␣ ͉ VCAM-1 ͉ E-selectin

TNFα induces ABCA1 through NF-κB in macrophages and in phagocytes ingesting apoptotic cells

“…Although some other studies have suggested a proatherogenic role of TNF␣ signaling, this role may depend on the cell type involved as well as the specific receptors and signaling pathways downstream of TNF␣. Thus, there seems to be abundant evidence for a proatherogenic role of TNF␣ signaling in endothelial cells (49,50). In contrast, TNF␣ signaling via NF-B in macrophages and smooth muscle cells may have antiatherogenic consequences.…”

Adenosine suppresses activation of nuclear factor-κB selectively induced by tumor necrosis factor in different cell types

“…The levels of adenosine used in our studies are not uncommon physiologically (Traut, 1994). Because of the critical role of NF-kB in a wide variety of diseases including cardiovascular diseases, RA and nephritis (Albrecht et al, 1995;Miagkov et al, 1998;Zwacka et al, 1998;Li et al, 1999Li et al, , 2000Hajra et al, 2000), the present study provides us another potential means of downregulating the activation of this transcription factor.…”

“…Most of these agents induce the phosphorylation-dependent degradation of IkBa proteins, allowing active NF-kB to translocate to the nucleus where it regulates gene expression. The activation of NF-kB has been detected in various inflammatory diseases, including RA, septic shock, and myocardial ischemia (Miagkov et al, 1998;Zwacka et al, 1998;Li et al, 1999;Hajra et al, 2000), known to be affected by adenosine. Since the expression of most inflammatory cytokines (e.g., TNF), known to be modulated by adenosine, is also regulated by NF-kB activation (Albrecht et al, 1995), we postulate that adenosine mediates its effects through suppression of NF-kB.…”

Shear Stress Regulates Endothelial Nitric-oxide Synthase Promoter Activity through Nuclear Factor κB Binding

“…Indeed, in lesion prone areas of the circulation there is increased expression of p65 as well as I K␣ and I K␤ (30). Interestingly, NO ⅐ has been shown to inhibit NF B activation via at least two mechanisms.…”