Very low-density lipoprotein activates nuclear factor-kappaB in endothelial cells.
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.
D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D001011:Aorta / Q000187:drug effects / Q000378:metabolism; D002460:Cell Line; D002914:Chylomicrons / Q000494:pharmacology; D004655:Emulsions; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D005230:Fatty Acids, Nonesterified / Q000494:pharmacology; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism; D007267:Injections; D008055:Lipids / Q000494:pharmacology; D008079:Lipoproteins, VLDL / Q000378:metabolism / Q000494:pharmacology / Q000502:physiology*; D008297:Male; D016328:NF-kappa B / Q000378:metabolism*; D010084:Oxidation-Reduction; D011341:Probucol / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley