Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P51812 (mitogen-activated protein)
 10,636 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Growth factor-stimulated DNA synthesis in a variety of cell lines has been shown to be decreased after overnight (or longer) treatment with the 3-hydroxy-3-methylglutaryl CoA reductase inhibitors, the statins. Although this anti-mitogenic effect had been presumed to be the result of the impairment of Ras lipidation, a stable modification (T1/2 approximately 20 h), this study provides new data demonstrating that brief (approximately 1 h) pretreatment of rat vascular smooth muscle cells with 100 microM pravastatin before platelet-derived growth factor-BB (PDGF-BB) stimulation results in attenuation of DNA synthesis through a Ras-independent mechanism. PDGF-BB-stimulated PDGF-beta receptor tyrosine phosphorylation, Ras activity, and mitogen-activated protein/extracellular signal-regulated kinase activity are unaffected by from 10 min to 1 h of pravastatin incubation, while Raf activity is markedly increased after 1 h of pravastatin. Phosphatidylinositol-3 kinase activity and phosphorylation of its downstream effector Akt are decreased after 1 h pravastatin incubation. Rho is stabilized by pravastatin, and ADP-ribosylation of Rho by C3 exoenzyme decreases PDGF-stimulated phosphatidylinositol-3 kinase activity, mimicking the effect of pravastatin on this signaling protein. Levels of the cyclin-dependent kinase inhibitor p27Kip1 are increased when cells were preincubated with pravastatin for 1 h and then exposed to PDGF, and apoptosis is induced by pravastatin incubation times as short as 1 to 4 h. Thus, short-term, high-dose pravastatin inhibits vascular smooth muscle cell growth and induces apoptosis independently of Ras, likely by means of the drug's effect on p27Kip1, mediated by Rho and/or phosphatidylinositol-3 kinase. This work demonstrates for the first time that the statins may be therapeutically useful when applied for short periods of time such that potential toxicity of long-term statin use (such as chronic Ras inhibition) may be avoided, suggesting future therapeutic directions for statin research.
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PMID:Short-term pravastatin mediates growth inhibition and apoptosis, independently of Ras, via the signaling proteins p27Kip1 and P13 kinase. 1047 39

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.
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PMID:Inhibitory effect of pitavastatin (NK-104) on the C-reactive-protein-induced interleukin-8 production in human aortic endothelial cells. 1570 Oct 58