PPARalpha activation abolishes LDL-stimulated IL-8 production via AP-1 deactivation in human aortic smooth muscle cells.
Native low density lipoprotein (n-LDL) is a major risk factor for cardiovascular diseases by inducing inflammatory processes and vascular smooth muscle cell proliferation in vessel cells. It has previously been reported that LDL enhances inflammatory reactions by the up-regulation of interleukin (IL)-8 via the activation of p38 kinase and activator protein (AP)-1 in human aortic smooth muscle cells (hAoSMCs). The findings of this study show, for the first time, that the peroxisome proliferator-activated receptor (PPARalpha) agonist, fenofibrate, completely abolishes the LDL-induced IL-8 up-regulation at the transcriptional level. Pretreatment of hAoSMCs with fenofibrate abolishes the effects of LDL on AP-1 activation without affecting nuclear factor (NF)-kappaB. In contrast, fenofibrate failed to modulate the activation state of p38 and JNK kinases or the levels of c-fos and phospho-Jun. These data suggest that AP-1 is likely to be located at the crossroads between LDL signaling and the regulation of IL-8 modulation by PPARalpha.
Ryoo
Sungwoo
S
Genomic Research Center, Korea Research Institute of Bioscience and Biotechnology, Yusong, Daejeon, Republic of Korea.
Won
Misun
M
Kim
Dong-Uk
DU
Kim
Lila
L
Han
Gyoonhee
G
Park
Seung-Kiel
SK
Mukaida
Naofumi
N
Maeng
Piljae
P
Yoo
Hyang-Sook
HS
Hoe
Kwang-Lae
KL
D001011:Aorta / Q000166:cytology; D002478:Cells, Cultured; D008078:Cholesterol, LDL / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D015536:Down-Regulation / Q000187:drug effects; D011345:Fenofibrate / Q000494:pharmacology; D017930:Genes, Reporter; D006801:Humans; D000960:Hypolipidemic Agents / Q000494:pharmacology; D016209:Interleukin-8 / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics; D048031:JNK Mitogen-Activated Protein Kinases; D008156:Luciferases / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists / Q000378:metabolism*; D018808:Transcription Factor AP-1 / Q000378:metabolism*; D014157:Transcription Factors / Q000819:agonists / Q000378:metabolism*; D014158:Transcription, Genetic / Q000187:drug effects; D014162:Transfection; D048051:p38 Mitogen-Activated Protein Kinases
D008078:Cholesterol, LDL; D000960:Hypolipidemic Agents; D016209:Interleukin-8; D016328:NF-kappa B; D016760:Proto-Oncogene Proteins c-fos; D018160:Receptors, Cytoplasmic and Nuclear; D018808:Transcription Factor AP-1; D014157:Transcription Factors; D008156:Luciferases; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D011345:Fenofibrate