Inflammatory response of human coronary artery endothelial cells to saturated long-chain fatty acids.
Saturated long-chain fatty acids (SFAs) exert unfavourable metabolic effects (lipotoxicity) and induce apoptotic cell death (lipoapoptosis) in certain cell-types. Their contribution to inflammatory cell responses is unclear. We studied the expression of 113 inflammatory genes in human coronary artery endothelial cells (hCAECs) and their regulation by SFAs and unsaturated long-chain fatty acids (UFAs). Gene regulation in hCAECs was assessed with macroarrays, real-time RT-PCR and immunoblotting. Participation of the transcription factor NFκB and the stress kinases JNK and p38 MAPK in gene-regulatory events was examined with pharmacological inhibitors. Based on macroarray data, 59 inflammatory genes were expressed in hCAECs, 14 were regulated by the SFA palmitate. SFA-triggered induction of IL1A, IL6, IL8, CXCL2, CXCL3, CCL20, SPP1 and CEBPB was confirmed by RT-PCR or immunoblotting. All gene inductions were SFA-specific. Using inhibitor SN50, palmitate-induced expression of IL8, CXCL3 and CCL20 was NFκB-dependent (all p<0.05). Furthermore, JNK was involved in palmitate-induced expression of IL1A, IL8, CXCL3, SPP1 and CEBPB as determined with inhibitor SP600125 (all p<0.05). Finally, the effectiveness of the tested fatty acids to induce inflammatory genes was closely reflected by their effectiveness to trigger endoplasmic reticulum stress. In conclusion, hCAECs express a large panel of inflammatory genes with a series of genes being regulated by palmitate and stearate, but not by UFAs. Thus, SFAs represent potential contributors to vascular inflammation.
Department of Internal Medicine, Division of Endocrinology, Diabetology, Angiology, Nephrology, and Clinical Chemistry, University Hospital Tübingen, Tübingen, Germany.
Alexander
A
Krogmann
Katrin
K
Staiger
Carina
C
Haas
Nadja
N
Gommer
Andreas
A
Peter
Martin
M
Heni
Fausto
F
Machicao
Hans-Ulrich
HU
Häring
Harald
H
Staiger
D022782:CCAAT-Enhancer-Binding Protein-beta / Q000235:genetics; D002478:Cells, Cultured; D054418:Chemokine CCL20 / Q000235:genetics; D019743:Chemokines, CXC / Q000235:genetics; D003331:Coronary Vessels / Q000166:cytology*; D015536:Down-Regulation / Q000187:drug effects / Q000235:genetics; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism*; D005227:Fatty Acids / Q000494:pharmacology*; D005231:Fatty Acids, Unsaturated / Q000494:pharmacology; D015870:Gene Expression / Q000187:drug effects / Q000235:genetics; D020869:Gene Expression Profiling; D006801:Humans; D007249:Inflammation / Q000139:chemically induced / Q000378:metabolism*; D053582:Interleukin-1alpha / Q000235:genetics; D053583:Interleukin-1beta / Q000494:pharmacology; D016209:Interleukin-8 / Q000235:genetics; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D019308:Palmitic Acid / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D013229:Stearic Acids / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D015854:Up-Regulation / Q000187:drug effects / Q000235:genetics
D022782:CCAAT-Enhancer-Binding Protein-beta; C108355:CCL20 protein, human; C545012:CEBPB protein, human; C499707:CXCL3 protein, human; D054418:Chemokine CCL20; D019743:Chemokines, CXC; D005227:Fatty Acids; D005231:Fatty Acids, Unsaturated; D053582:Interleukin-1alpha; D053583:Interleukin-1beta; D016209:Interleukin-8; D016328:NF-kappa B; D013229:Stearic Acids; D014409:Tumor Necrosis Factor-alpha; D019308:Palmitic Acid; C031183:stearic acid; D048031:JNK Mitogen-Activated Protein Kinases