Endothelial Cell-Specific NF-κB Inhibition Protects Mice from Atherosclerosis

Abstract

Atherosclerosis is a progressive disorder of the arterial wall and the underlying cause of cardiovascular diseases such as heart attack and stroke. Today, atherosclerosis is recognized as a complex disease with a strong inflammatory component. The nuclear factor-kappaB (NF-kappaB) signaling pathway regulates inflammatory responses and has been implicated in atherosclerosis. Here, we addressed the function of NF-kappaB signaling in vascular endothelial cells in the pathogenesis of atherosclerosis in vivo. Endothelium-restricted inhibition of NF-kappaB activation, achieved by ablation of NEMO/IKKgamma or expression of dominant-negative IkappaBalpha specifically in endothelial cells, resulted in strongly reduced atherosclerotic plaque formation in ApoE(-/-) mice fed with a cholesterol-rich diet. Inhibition of NF-kappaB abrogated adhesion molecule induction in endothelial cells, impaired macrophage recruitment to atherosclerotic plaques, and reduced expression of cytokines and chemokines in the aorta. Thus, endothelial NF-kappaB signaling orchestrates proinflammatory gene expression at the arterial wall and promotes the pathogenesis of atherosclerosis.

Long non-coding RNA ANRIL regulates inflammatory responses as a novel component of NF-κB pathway

“…It should be further realized that besides CAD, other human diseases associated with Chr9p21 including cancers and periodontitis are also complex chronic immune disorders with aberrated NF-kB signaling 54 and the current finding might shed light on the illustration of ANRIL/NF-kB function in these diseases as well. Since blocking NF-kB signaling in endothelial cells has been shown to significantly protect against atherosclerosis, 42 ANRIL as a downstream modulator of NF-kB might be explored to establish whether it can act as a more specific target for drug development.…”

“…40 NF-kB is also a converged molecule acting as both a responder and regulator of the inflammatory factors linked to endothelial activation and atherosclerosis. 41,42 Recently characterized lncRNAs including Lethe and lincRNA-Cox2 are all linked to regulation of NF-kB activity 43,44 and manipulation of inflammatory signaling. Data presented in this study explicitly demonstrate that ANRIL is not only a novel downstream target of NF-kB in vascular ECs, but also a modulator of other genes downstream of NF-kB in addition to other known components of this pathway.…”

Rap1 induces cytokine production in pro-inflammatory macrophages through NFκB signaling and is highly expressed in human atherosclerotic lesions

“…17,38,39 In human atheroma, endothelial cells and smooth muscle cells also elaborate cytokines and contribute to the overall inflammatory state. 40,41 Therefore, it was logical to test whether or not reduced Rap1 levels can diminish the release of NFkB-mediated pro-inflammatory mediators in endothelial and vascular smooth muscle cells. Modulation of Rap1 levels had no effect on IL-8, IL-1b, ICAM-1, VCAM-1, E-selectin and Pselectin expression in activated endothelial cells and did not affect IL-8, IL-1b, M-CSF and GM-CSF expression in vascular smooth muscle cells.…”

G Protein-Coupled Receptor Dependent NF-κB Signaling in Atherogenesis

“…The CARMA3/Bcl10/MALT1 signalosome and endothelial phenotype 6.1 Role for endothelial NF-κB activation in atherogenesis As discussed earlier, many pieces of evidence implicate endothelial cell NF-B activation as an important GPCR-mediated signaling event favoring atherogenesis. Recently, this concept was reinforced by elegant studies using two related mouse models (Gareus et al, 2008). These researchers first generated an endothelial-specific IKK  -/-mouse, to disrupt any NF-B signaling in this cell type.…”