Inhibitory effect of pitavastatin (NK-104) on the C-reactive-protein-induced interleukin-8 production in human aortic endothelial cells.
Recent data have indicated that CRP (C-reactive protein) plays a role in atherosclerosis, in addition to being a marker for inflammatory diseases. IL-8 (interleukin-8), a CXC chemokine, is present in human coronary atheroma and promotes monocyte-endothelial cell adhesion. In the present study, we examined the effect of pitavastatin (NK-104), a synthetic statin (3-hydroxy-3-methylglutaryl CoA reductase inhibitor), on IL-8 production induced by CRP in human AoEC (aortic endothelial cells). We also investigated whether CRP can induce IL-8 production and if the activation of signalling pathways are functionally related. The concentrations of IL-8 in the media after stimulation with CRP were measured by ELISA, and the expression of IL-8 mRNA was assessed by Northern blot. The phosphorylation of MAPKs (mitogen-activated protein kinases) was determined by Western blot. The production of IL-8 induced by CRP (10 microg/ml) was enhanced significantly and was inhibited by pitavastatin. The expression of IL-8 mRNA was increased in a dose-dependent manner after stimulation with CRP (1-100 microg/ml), whereas expression of IL-8 mRNA induced by CRP (50 microg/ml) was significantly diminished by 5 microM pitavastatin. Furthermore, specific MAPK inhibitors (PD98059, SB203580 and SP600125) inhibited the expression of IL-8 mRNA induced by CRP (50 microg/ml). The phosphorylation of all three MAPKs [ERK (extracellular-signal-regulated kinase), p38 MAPK and JNK (c-Jun N-terminal kinase)] induced by CRP (10 microg/ml) was also significantly inhibited by pitavastatin. Our results suggest that CRP may play a role in atherosclerosis via IL-8 production and pitavastatin may prevent the progression of atherosclerosis not only by lowering plasma low-density lipoprotein cholesterol levels, but also by suppressing IL-8 production in endothelial cells through the inhibition of MAPK (ERK, p38 MAPK and JNK) pathways.
Kibayashi
Etsuko
E
First Department of Internal Medicine, School of Medicine, Toyama Medical and Pharmaceutical University, 2630 Sugitani, Toyama 930-0194, Japan.
Urakaze
Masaharu
M
Kobashi
Chikaaki
C
Kishida
Mika
M
Takata
Michiyo
M
Sato
Akira
A
Yamazaki
Katsuya
K
Kobayashi
Masashi
M
D000704:Analysis of Variance; D001011:Aorta; D001161:Arteriosclerosis / Q000276:immunology; D015152:Blotting, Northern / Q000379:methods; D015153:Blotting, Western / Q000379:methods; D002097:C-Reactive Protein / Q000378:metabolism*; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism*; D004730:Endothelium, Vascular / Q000187:drug effects / Q000276:immunology*; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D016209:Interleukin-8 / Q000378:metabolism*; D011804:Quinolines / Q000494:pharmacology*
D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D016209:Interleukin-8; D011804:Quinolines; D002097:C-Reactive Protein; C108475:pitavastatin