Very low-density lipoprotein activates nuclear factor-kappa B in endothelial cells

High plasma levels of VLDL are associated with increased risk for atheroscl erosis. Here we show that VLDL (75 to 150 mu g/mL) activates nuclear factor -kappa B (NF-kappa B), a transcription factor known to play a key role in r egulation of inflammation. Oxidation of VLDL reduced its capacity to activa te NF-kappa B in vitro, whereas free fatty acids such as linoleic and oleic acid activated NF-kappa B to the same extent as did VLDL. Intravenous inje ction of human VLDL (6 mg protein per kg) into rats resulted in arterial ac tivation of NF-kappa B as assessed by electrophoretic mobility shift assay. Aortic endothelial cells showed positive nuclear staining for the activate d RelA (p65) subunit of NF-kappa B at 6 to 24 hours after injection. There was also a parallel expression of the adhesion molecules intercellular adhe sion molecule-1 and vascular cell adhesion molecule-1, as well as the cytok ine tumor necrosis factor-alpha. Pretreatment of the rats with diet contain ing 1% of the antioxidant probucol for 8 weeks did not inhibit arterial act ivation of NF-kappa B in response to injection of VLDL. Moreover, injection of triglycerides (10% Intralipid, 5 mL/kg) activated arterial expression o f NF-kappa B to the same extent as VLDL. Our results suggest that VLDL may promote the development of atherosclerotic lesions by activation of the pro inflammatory transcription factor NF-kappa B. The effect appears to be medi ated by a release of VLDL fatty acids but not to involve VLDL oxidation.