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)

It is not certain whether activation of the Ras/mitogen-activated protein (MAP) kinase pathway is involved in cardiac hypertrophy. 3-Hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors, such as lovastatin, prevent farnesylation of the Ras protein, which is critical for Ras's membrane localization and function. Therefore, the present study was undertaken to investigate the role of the Ras pathway, which is linked to mevalonate metabolism, in the mechanism of stretch-induced myocyte hypertrophy. Myocytes isolated from 1- to 2-day-old rats were cultured at 4.1 x 10(6) cells per well in a deformable silicon dish and incubated with serum-free medium for 7 days. The cultures were stretched by 15% on culture day 4. Stretch increased the RNA/DNA ratio by 20% to 26% on culture days 5 and 6 and the protein/DNA ratio by 18% to 20% on culture days 6 and 7. Stretch accelerated rates of protein synthesis by 24% on culture day 6. Stretch increased protein kinase C (PKC) activity, MAP kinase activity, and c-fos mRNA expression. A selective PKC inhibitor, calphostin C (1 x 10(-6) M), prevented the stretch-induced increase in PKC activity, but lovastatin (7.5 x 10(-6) M) did not. Lovastatin as well as calphostin C partially but significantly inhibited the stretch-induced increases in MAP kinase activity, c-fos mRNA expression, and protein synthesis. Pretreatment with both lovastatin and calphostin C completely inhibited the increases in these variables caused by stretch. Lovastatin as well as calphostin C prevents stretch-induced cardiac hypertrophy. These results suggest that mechanical stretch may activate the Ras pathway, which is linked to mevalonate metabolism, in cultured neonatal rat heart cells.
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PMID:Mechanical stretch activates a pathway linked to mevalonate metabolism in cultured neonatal rat heart cells. 966 7

Statins, which competitively inhibit 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase activity and reduce mevalonate synthesis, are believed to exert a plethora of pleiotropic effects. In this report, molecular mechanisms of the inhibitory effect on plasminogen activator inhibitor type 1 (PAI-1) expression produced by cerivastatin (CRV), the most active compound in this class, were studied using monocultures of human endothelial cell line (EA.hy 926). CRV similar to another statin, lovastatin (LOV), significantly inhibited PAI-1 expression and its release from endothelial cells, nonstimulated and stimulated with TNF-alpha. The inhibitory effect of CRV could be detected at the level of PAI-1 promoter in EA.hy 926 cells transfected with plasmid p800 LUC containing PAI-1 promoter fragment (+71 to -800), as well as at the level of PAI-1 mRNA. The PAI-1 promoter activity was markedly suppressed in the nonstimulated cells and almost completely inhibited in TNF-alpha-stimulated cells. In addition, CRV at low doses (IC(50) of 4 - 6 microM) significantly inhibited mitogen-activated protein kinases (MAPKs) phosphorylation. The majority of inhibitory effects occurred at significantly lower concentrations for CRV compared to LOV. The mechanism by which CRV inhibits PAI-1 expression appears to be directly associated with geranylgeranylation of some cell proteins, since the inhibitory effect on PAI-1 expression can be reversed by geranylgeranyl-pyrophosphate but not by farnesyl-pyrophosphate.
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PMID:Cerivastatin, a HMG-CoA reductase inhibitor, reduces plasminogen activator inhibitor-1 (PAI-1) expression in endothelial cells by down-regulation of cellular signaling and the inhibition of PAI-1 promoter activity. 1250 Oct 10

Statins, specific inhibitors of 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase, are now widely used for treatment of patients with hypercholesterolemia. In addition to the reduction of cholesterol biosynthesis, accumulating evidence indicates that statins have several pleiotropic effects especially on cardiovascular system. However, the exact role of statin in cardiac myocytes remains unclear. In the present study, we investigated whether atorvastatin induces vascular endothelial growth factor (VEGF) release in cardiac myocytes, and the underlying mechanism. We observed that atorvastatin significantly stimulated VEGF release in a dose-dependent manner. It induced the phosphorylation of p44/p42 mitogen-activated protein (MAP) kinase and p38 MAP kinase but not SAPK (stress-activated protein kinase)/JNK (c-Jun N-terminal kinase). The atorvastatin-induced VEGF release was enhanced by PD98059, which is a specific inhibitor of the upstream kinase that activates p44/p42 MAP kinase (MEK). Further, it was significantly reduced by SB203580, a specific inhibitor of p38 MAP kinase. Furthermore, the atorvastatin-induced phosphorylation of p38 MAP kinase was attenuated by SB203580, whereas it was enhanced by PD98059. Taken together, these results suggest that the atorvastatin-induced VEGF release in cardiac myocytes is positively regulated by p38 MAP kinase and negatively regulated byp44/p42 MAP kinase and that the atorvastatin-induced phosphorylation of p38 MAP kinase is regulated by p44/p42 MAP kinase in these cells.
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PMID:Differential roles of MAP kinases in atorvastatin-induced VEGF release in cardiac myocytes. 1670 7

Chronic pancreatitis (CP) is characterized by progressive fibrosis, pain and/or loss of exocrine and endocrine functions. Recent in vitro and in vivo experiments have proven objectively the role of activated pancreatic stellate cells (PSC) in fibrogenesis in CP. Molecular mediators shown to regulate the pathogenesis include transforming growth factor beta (TGF-beta), platelet-derived growth factor (PDGF), and pro-inflammatory cytokines such as IL-1, IL-6 and TNF-alpha. Furthermore, molecular pathways involving mitogen-activated protein kinases (MAPK), phosphatidyl inositol 3-kinase (PI3K), Ras superfamily G proteins, serine threonine protein kinase Raf-1 and peroxisome proliferator activated receptor gamma (PPAR-gamma) have been elucidated. Understanding of the pathogenesis has led to identification of novel molecular targets and development of potential newer therapeutic agents. Those found to retard the progression of experimental CP and fibrosis in animal models include interferon (IFN) beta and IFN-gamma; a Japanese herbal medicine called Saiko-keishi-to (TJ-10); curcumin; PPAR-gamma ligand (troglitazone); antioxidants (vitamin A, vitamin E, DA 9601 and epigallocatechin-3-gallate); a protease inhibitor (camostat mesilate) and hydroxymethylglutaryl-CoA inhibitor (lovastatin). This review summarizes the current literature addressing the role of different pharmacological agents aimed at reducing or preventing inflammation and the consequent fibrogenesis in CP.
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PMID:Pancreatic stellate cells: new target in the treatment of chronic pancreatitis. 1799 43