Fatty acid—Mediated activation of vascular endothelial cells

• Published in: Metabolism, clinical and experimental Vol. 49; no. 8; pp. 1006 - 1013
• Main Authors: Hennig, Bernhard, Meerarani, Purushothaman, Ramadass, Pachaikani, Watkins, Bruce A., Toborek, Michal
• Format: Journal Article
• Language: English
• Published: New York, NY Elsevier Inc 01-08-2000; Elsevier
• Subjects: alpha-Linolenic Acid - pharmacology; Animals; Atherosclerosis (general aspects, experimental research); Biological and medical sciences; Blood and lymphatic vessels; Cardiology. Vascular system; Cells, Cultured; Endothelium, Vascular - drug effects; Endothelium, Vascular - metabolism; Endothelium, Vascular - physiology; Fatty Acids, Unsaturated - pharmacology; Gene Expression Regulation - drug effects; Glutathione - metabolism; Interleukin-6 - biosynthesis; Linoleic Acid - pharmacology; Medical sciences; NF-kappa B - physiology; Oleic Acid - pharmacology; Oxidation-Reduction; Oxidative Stress - physiology; Pulmonary Artery - cytology; Pulmonary Artery - drug effects; Pulmonary Artery - physiology; Stearic Acids - pharmacology; Structure-Activity Relationship; Swine; Cell culture; Endothelial cell; Pathogenesis; Cardiovascular disease; Activation; Biosynthesis; Fatty acids; Biological activity; Vascular disease; Vertebrata; Mammalia; Swine; Animal; Atherosclerosis; Artiodactyla; Transcription factor NFκB; Transcription factor; Ungulata; Glutathione
• ISSN: 0026-0495; 1532-8600
• DOI: 10.1053/meta.2000.7736

Vascular endothelial cell activation and dysfunction are critical early events in atherosclerosis. Selected dietary lipids (eg, fatty acids) may be atherogenic by activating endothelial cells and by potentiating an inflammatory response. Due to their prooxidant property, unsaturated fatty acids may play a critical role in endothelial cell activation and injury. To test this hypothesis, porcine endothelial cells were exposed to 18-carbon fatty acids differing in the degree of unsaturation, ie, 90 μmol/L stearic (18:0), oleic (18:1n-9), linoleic (18:2n-6), or linolenic acid (18:3n-3) for 6 to 24 hours and/or tumor necrosis factor alpha ([TNF-α] 500 U/L) for up to 3 hours. Compared with control cultures, treatment with 18:0 and 18:2 decreased glutathione levels, suggesting an increase in cellular oxidative stress. Both 18:2 and 18:0 activated the transcription factor nuclear factor κB (NF-κB) the most and 18:1 the least. This NF-κB—dependent transcription was confirmed in endothelial cells by luciferase reporter gene assay. The fatty acid—mediated activation of NF-κB was blocked by preenrichment of the cultures with 25 μmol/L vitamin E. All fatty acids except 18:1 and 18:3 increased transendothelial albumin transfer, and 18:2 caused the most marked disruption of endothelial integrity. Preenrichment of endothelial cells with 18:2 followed by exposure to TNF-α resulted in a 100% increase in interleukin-6 (IL-6) production compared with TNF-α exposure alone. In contrast, cellular preenrichment with 18:0, 18:1, or 18:3 had no effect on TNF-α—mediated production of IL-6. Cellular release of radiolabeled arachidonic acid (20:4) was markedly increased only by cell exposure to 18:2 and 18:3, and the release of 20:4 appeared to be mainly from the phosphatidylethanolamine fraction. These data suggest that oleic acid does not activate endothelial cells. Furthermore, linoleic acid and other omega-6 fatty acids appear to be the most proinflammatory and possibly atherogenic fatty acids.