Very Low-Density Lipoprotein Activates Nuclear Factor-κB in Endothelial Cells

Abstract

High plasma levels of VLDL are associated with increased risk for atherosclerosis. Here we show that VLDL (75 to 150 microg/mL) activates nuclear factor-kappaB (NF-kappaB), a transcription factor known to play a key role in regulation of inflammation. Oxidation of VLDL reduced its capacity to activate NF-kappaB in vitro, whereas free fatty acids such as linoleic and oleic acid activated NF-kappaB to the same extent as did VLDL. Intravenous injection of human VLDL (6 mg protein per kg) into rats resulted in arterial activation of NF-kappaB as assessed by electrophoretic mobility shift assay. Aortic endothelial cells showed positive nuclear staining for the activated RelA (p65) subunit of NF-kappaB at 6 to 24 hours after injection. There was also a parallel expression of the adhesion molecules intercellular adhesion molecule-1 and vascular cell adhesion molecule-1, as well as the cytokine tumor necrosis factor-alpha. Pretreatment of the rats with diet containing 1% of the antioxidant probucol for 8 weeks did not inhibit arterial activation of NF-kappaB in response to injection of VLDL. Moreover, injection of triglycerides (10% Intralipid, 5 mL/kg) activated arterial expression of NF-kappaB to the same extent as VLDL. Our results suggest that VLDL may promote the development of atherosclerotic lesions by activation of the proinflammatory transcription factor NF-kappaB. The effect appears to be mediated by a release of VLDL fatty acids but not to involve VLDL oxidation.

The Renin-Angiotensin System Is Involved in the Production of Plasminogen Activator Inhibitor Type 1 by Cultured Endothelial Cells in Response to Chylomicron Remnants

“…Chylomicron remnants can provoke oxidative stress (40,41), and oxidative stress can in turn activate NF-κB (42). We determined NF-κB activation induced by chylomicron remnants, and found that the NF-κB activation was consistent with the results obtained by VLDL (43). According to a recent report, remnant like lipoprotein particles from patients with type III hyperlipoproteinemia induce endothelial cell PAI-1 expression (44).…”

Genome-Wide Linkage Analysis of Serum Adiponectin in the Pima Indian Population

“…Interestingly, chromosome 9p is the site of the VLDL receptor, which is expressed in adipose tissue (47) and is believed to influence uptake of free fatty acids into peripheral tissues including adipose (48). VLDL may also have proinflammatory actions, increasing cytokine secretion (49) and activating nuclear transcription factor-B, the key signaling pathway in inflammatory response (50). Adiponectin is believed to exert anti-inflammatory actions by inhibition of the same nuclear transcription factor-B pathway (46).…”

Are Oxidative Stress−Activated Signaling Pathways Mediators of Insulin Resistance and β-Cell Dysfunction?

“…This latter situation is exacerbated because FFAs are not only capable of inducing oxidative stress, but also impair endogenous antioxidant defenses by reducing intracellular glutathione (36,71,72). Numerous in vitro studies have reported FFA-mediated activation of NF-B, a likely consequence of the ability of FFAs to increase ROS formation and reduce glutathione (72)(73)(74)(75). This effect might be also linked to FFA-mediated activation of PKC- (76), which has the unique ability among PKC isoforms to activate NF-B (77).…”