Pravastatin suppresses the interleukin-8 production induced by thrombin in human aortic endothelial cells cultured with high glucose by inhibiting the p44/42 mitogen activated protein kinase.
1. 3-Hydroxy-3-methylglutaryl co-enzyme A reductase inhibitors (statins) prevent the progression of atherosclerosis by lowering cholesterol. However, the effect of statins on the synthesis of pro-inflammatory cytokines from endothelial cells has not yet been fully investigated. Here, we examined the effect of pravastatin, one of the statins, on IL-8 synthesis induced by thrombin in human aortic endothelial cells (AoEC) cultured with high glucose concentrations. 2. Pravastatin significantly decreased the IL-8 synthesis induced by thrombin. 3. Pravastatin inhibited the p44/42 MAP kinase activity induced by thrombin, but did not inhibit the p38 MAP kinase activity. 4. Translocation of ras protein from the cytosol to plasma membrane was inhibited by pravastatin. 5. Pravastatin inhibit the activator protein-1 activity, but did not inhibit the activation of IkappaB-alpha. 6. Dominant negative ras inhibited the p44/42 MAP kinase activity induced by PMA. 7. Our results suggest that pravastatin inhibits IL-8 synthesis by blocking the ras-MAP (p44/42) kinase pathway rather than nuclear factor-kappaB. Pravastatin may prevent atherosclerosis not only by lowering cholesterol levels, but also by suppressing IL-8 synthesis in AoEC through the inhibition of p44/42 MAP kinase, and this may be more beneficial in diabetic patients than in non-diabetics.
Takata
M
M
First Department of Internal Medicine, School of Medicine, Toyama Medical and Pharmaceutical University, 2630 Sugitani, Toyama 930-0194, Japan.
Urakaze
M
M
Temaru
R
R
Yamazaki
K
K
Nakamura
N
N
Nobata
Y
Y
Kishida
M
M
Sato
A
A
Kobayashi
M
M
D000924:Anticholesteremic Agents / Q000494:pharmacology; D001011:Aorta / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D015153:Blotting, Western; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000187:drug effects / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D005947:Glucose / Q000494:pharmacology*; D006801:Humans; D020672:I-kappa B Proteins; D016209:Interleukin-8 / Q000096:biosynthesis* / Q000235:genetics; D019950:Mitogen-Activated Protein Kinase 1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000072000:NF-KappaB Inhibitor alpha; D010766:Phosphorylation / Q000187:drug effects; D010940:Plant Proteins; D017035:Pravastatin / Q000494:pharmacology*; D012333:RNA, Messenger / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D013917:Thrombin / Q000494:pharmacology*; D018808:Transcription Factor AP-1 / Q000187:drug effects / Q000378:metabolism; D018631:ras Proteins / Q000187:drug effects / Q000378:metabolism
D000924:Anticholesteremic Agents; D004268:DNA-Binding Proteins; D020672:I-kappa B Proteins; D016209:Interleukin-8; C000606204:NFKBIA protein, human; D010940:Plant Proteins; D012333:RNA, Messenger; D018808:Transcription Factor AP-1; D000072000:NF-KappaB Inhibitor alpha; C101691:MMK4 protein, Medicago sativa; D019950:Mitogen-Activated Protein Kinase 1; D020928:Mitogen-Activated Protein Kinases; D013917:Thrombin; D018631:ras Proteins; D005947:Glucose; D017035:Pravastatin; D013755:Tetradecanoylphorbol Acetate