Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.7.12.2 (MEK)
18,161 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

One mechanism by which high density lipoproteins (HDLs) exert their protective effect against coronary artery disease could be related to the induction of prostacyclin (PGI(2)) release in the vessel wall. We have recently shown that HDL increases PGI(2) production in rabbit smooth muscle cells (RSMCs) and that this increase is dependent on cyclooxygenase-2 (Cox-2). Here we analyze the mechanism by which rabbit HDL induces PGI(2) release in RSMCs. Our results show that although HDL(2) and HDL(3) share a similar capacity to induce Cox-2 protein levels, HDL(3) stimulates a higher PGI(2) release than does HDL(2), probably because of their relative arachidonate contents. Acetylsalicylic acid pretreatment (300 micromol/L, 30 minutes) significantly reduced the HDL-induced PGI(2) release, suggesting that both preexisting and induced Cox-2 activities were involved in the HDL effect. Ca(2+)-dependent cytosolic phospholipase A(2) (cPLA(2)) and Cox-1 protein levels were not altered by HDL. Dexamethasone (2 micromol/L), which also inhibited the HDL-induced PGI(2) release, reduced significantly both Cox-2 mRNA and protein levels without affecting cPLA(2) and Cox-1 protein levels. In addition, methylarachidonyl fluorophosphonate, a potent inhibitor of cPLA(2), did not produce any effect on HDL-induced PGI(2) release. In the presence of cycloheximide, Cox-2 mRNA levels were induced by HDL and inhibited by dexamethasone, suggesting that HDL and dexamethasone work in the absence of de novo protein synthesis. These results indicate an early effect of HDL on PGI(2) biosynthesis, specifically increasing Cox-2. PD98059, an inhibitor of mitogen-activated protein kinase kinase, completely inhibited HDL-induced PGI(2) release, whereas GF109203X, a protein kinase C inhibitor, had no effect. Thus, HDL induces PGI(2) synthesis by a mechanism dependent on the mitogen-activated protein kinase pathway but independent of protein kinase C.
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PMID:Regulatory effects of HDL on smooth muscle cell prostacyclin release. 1052 70

We reported previously that vascular endothelial growth factor (VEGF) stimulates prostacyclin (PGI(2)) production via activation of the extracellular signal-regulated kinase (ERK) cascade. In this paper, we examined the role of protein kinase C (PKC) in this pathway. VEGF-induced PGI(2) generation and arachidonic acid release in human umbilical vein endothelial cells were inhibited by the PKC inhibitors GF109203X and calphostin C. VEGF increased PKC activity and immunoreactivity of the PKCdelta, alpha and epsilon isoforms in particulate fractions of cells. PKC inhibitors blocked VEGF-induced activation of ERK, MEK (mitogen-activated protein kinase kinase) and the cytosolic phospholipase A(2), but had little effect on ERK activation induced by basic fibroblast growth factor. GF109203X, calphostin C and the PKCdelta-selective inhibitor, rottlerin, did not inhibit activation of the KDR receptor for VEGF. Inhibition of Ca(2+) fluxes using BAPTA/AM [1,2-bis-(o-aminophenoxy)ethane-N,N,N',N'-tetra-acetic acid tetrakis(acetoxymethyl ester)] blocked VEGF-induced PGI(2) production but did not inhibit ERK activation. Neither activation nor inhibition of the NO/cGMP pathway had any effect on VEGF induction of ERK activity and PGI(2) synthesis. Wortmannin partially inhibited VEGF stimulation of PGI(2) production, but did not inhibit VEGF-induced ERK activity. VEGF-induced ERK activation and PGI(2) production were blocked by rottlerin, and VEGF increased association of PKCdelta with Raf-1, the upstream activator of MEK. The PKC-selective inhibitor Go6976 did not inhibit ERK activation and had only a partial effect on PGI(2) production. These findings indicate that activation of PKC plays a crucial role in VEGF signalling via the ERK cascade leading to PGI(2) synthesis and suggest that the PKCdelta isoform may be a key mediator of VEGF-induced activation of the ERK pathway via increased association with Raf-1.
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PMID:Vascular endothelial growth factor-induced prostacyclin production is mediated by a protein kinase C (PKC)-dependent activation of extracellular signal-regulated protein kinases 1 and 2 involving PKC-delta and by mobilization of intracellular Ca2+. 1117 Oct 46

We have examined the mechanisms regulating prostacyclin (PGI(2)) synthesis after acute exposure of human umbilical vein endothelial cells (HUVEC) to interleukin-1 alpha (IL-1 alpha). IL-1 alpha evoked an early (30 min) release of PGI(2) and [(3)H]arachidonate that was blocked by the cytosolic phospholipase A(2)alpha (cPLA(2)alpha) inhibitor arachidonyl trifluoromethyl ketone. IL-1 alpha-mediated activation of extracellular signal-regulated kinase 1/2 (ERK1/2; p42/p44(mapk)) coincided temporally with phosphorylation of cPLA(2)alpha and with the onset of PGI(2) synthesis. The mitogen-activated protein kinase (MAPK) kinase (MEK) inhibitors, PD-98059 and U-0126, blocked IL-1 alpha-induced ERK activation and partially attenuated cPLA(2)alpha phosphorylation and PGI(2) release, suggesting that ERK-dependent and -independent pathways regulate cPLA(2)alpha phosphorylation. SB-203580 treatment enhanced IL-1 alpha-induced MEK, p42/44(mapk), and cPLA(2)alpha phosphorylation but reduced thrombin-stimulated MEK and p42/44(mapk) activation. IL-1 alpha, but not thrombin, activated Raf-1 as assessed by immune-complex kinase assay, as did SB-203580 alone. These results show that IL-1 alpha causes an acute upregulation of PGI(2) generation in HUVEC, establish a role for the MEK/ERK/cPLA(2)alpha pathway in this early release, and provide evidence for an agonist-specific cross talk between p38(mapk) and p42/44(mapk) that may reflect receptor-specific differences in the signaling elements proximal to MAPK activation.
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PMID:Agonist-specific cross talk between ERKs and p38(mapk) regulates PGI(2) synthesis in endothelium. 1154 64

The first step in prostacyclin (PGI(2)) synthesis involves the generation of arachidonic acid (AA) from membrane phospholipids mediated by the 85 kDa cytosolic phospholipase A(2) (cPLA(2)alpha). The current study examined the effects of secretory PLA(2)s (sPLA(2)s) on PGI(2) production by human umbilical vein endothelial cells (HUVEC). We demonstrate that exposure of HUVEC to sPLA(2) dose- and time-dependently enhances AA release and PGI(2) generation. sPLA(2)-stimulated AA mobilisation was blocked by AACOCF(3), an inhibitor of cPLA(2)alpha, suggesting cross-talk between the two classes of PLA(2). sPLA(2) induced the phosphorylation of cPLA(2)alpha and enhanced the phosphorylation states of p42/44(mapk), p38(mapk), and JNK, concomitant with elevated AA and PGI(2) release. The MEK inhibitor PD98059 attenuated sPLA(2)-stimulated cPLA(2)alpha phosphorylation and PGI(2) release. These data show that sPLA(2) cooperates with cPLA(2)alpha in a MAPK-dependent manner to regulate PGI(2) generation and suggests that cross-talk between sPLA(2) and cPLA(2)alpha is a physiologically important mechanism for enhancing prostanoid production in endothelial cells.
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PMID:sPLA(2) cooperates with cPLA(2)alpha to regulate prostacyclin synthesis in human endothelial cells. 1157 47

Prostacyclin (PGI(2)) is a key mediator of pulmonary vasodilation during perinatal cardiopulmonary transition, at a time when fetal plasma estrogen levels are rising. We have previously shown that estradiol-17beta (E(2)) rapidly stimulates nitric oxide production by ovine fetal pulmonary artery endothelial cells (PAEC), and that this occurs through nongenomic mechanisms which are calcium- and tyrosine kinase-mitogen-activated protein (MAP) kinase-dependent. In the present study, we determined if E(2) acutely activates PGI(2) production in PAEC. E(2) (10(-8) M for 15 min) caused a 52% increase in PGI(2), the threshold concentration was 10(-10) M E(2), the effect occurred within 5 min, and it was not related to changes in cyclooxygenase type 1 (COX-1) or COX-2 abundance. Estrogen receptor (ER) alpha and ER beta proteins and mRNAs were found to be constitutively expressed in PAEC, and PGI(2) stimulation with E(2) was fully blocked by both ER antagonism with ICI 182,780, which is not selective for either ER isoform, and the ER beta-specific antagonist RR-tetrahydrochrysene. The rapid response to E(2) was also inhibited by calcium chelation, whereas genistein- or PD98059-induced inhibition of tyrosine kinase and MAP kinase kinase, respectively, had no effect. Thus, E(2) causes rapid stimulation of PGI(2) synthesis in fetal PAEC, this process is mediated by ER beta, and it is calcium-dependent and tyrosine kinase-MAP kinase-independent. These mechanisms may play a role in pulmonary vasodilation in the perinatal period.
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PMID:Estrogen acutely activates prostacyclin synthesis in ovine fetal pulmonary artery endothelium. 1197 Sep 14

1 Endothelial cells play an important role in the modulation of vascular tone because of their ability to produce vasoactive substances such as prostacyclin (PGI(2)). Cell-cell contact between human umbilical vein endothelial cells (HUVEC) and peripheral blood lymphocytes has been shown to stimulate endothelial PGI(2) synthesis by increasing free arachidonic acid availability through endothelial cytosolic phospholipase A2 (cPLA(2)) activation. In this study, we sought to determine whether phospholipase C (PLC) and D (PLD) activation also contributes, besides cPLA(2), to the lymphocyte-induced PGI(2) synthesis in HUVEC, and to delineate further the potential mechanisms of cPLA(2) activation triggered by the interaction of HUVEC with lymphocytes. 2 Pretreatment of endothelial cells with the PI-PLC inhibitor U-73122 before the coincubation with lymphocytes markedly inhibited the PGI(2) output whereas the diacylglycerol (DAG) lipase inhibitor RHC 80267 and ethanol had no effect. These results suggest that PLC may be involved through inositol trisphosphate generation and calcium mobilization, and that neither DAG nor phosphatidic acid (PtdOH) was used as sources of arachidonic acid. 3 The stimulated PGI(2) synthesis was protein kinase C (PKC)-independent but strongly inhibited by the mitogen-activated protein kinase kinase (MEK) inhibitors PD98059 and U-0126 and by the Src kinase inhibitor PP1. 4 Immunoblot experiments showed an increased phosphorylation of the extracellular signal-regulated kinases 1/2 (ERK1/2) upon lymphocyte addition till 4 h coincubation. Phosphorylation was markedly inhibited by U-0126 and PP1 addition. 5 Collectively, these results suggest that the signaling cascade triggered by lymphocytes in endothelial cells involves an Src kinase/ERK1/2 pathway leading to endothelial cPLA(2) activation.
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PMID:Mechanisms involved in the stimulation of prostacyclin synthesis by human lymphocytes in human umbilical vein endothelial cells. 1277 Sep 37

High density lipoproteins (HDL) induce prostacyclin (PGI(2)) release in vascular smooth muscle cells (VSMC) by up-regulation of cyclooxygenase-2 (Cox-2). Our goal was to analyse the mechanisms underlying this effect, and its potential modulation by HMG-CoA reductase inhibition in human VSMC. The contribution of mitogen-activated protein kinase (MAPK) signalling pathways was assessed by Western blot analysis and using specific inhibitors [PD098059 for p42/44 MAPK kinase (MEK); SB203580 for p38 MAPK or L-JNKI1 for c-Jun N-terminal kinase-1 (JNK-1)]. HDL-induced PGI(2) release was inhibited by rofecoxib (a specific Cox-2 inhibitor, 5 microM). HDL induced the early activation of p42 MAPK, p38 MAPK and JNK-1. p42/44 MAPK was the major pathway involved in both Cox-2 up-regulation and PGI(2) synthesis; p38 MAPK was also involved in both processes while JNK inhibition only affected PGI(2) synthesis. Pertussis toxin (an inhibitor of Galphai/Galphao proteins) prevented MAPK activation and inhibited both Cox-2 up-regulation and PGI(2) release. Genistein (a tyrosine kinase inhibitor) inhibited PGI(2) release without affecting MAPK activation or Cox-2 up-regulation. Simvastatin (0.1-1 microM) increased HDL-induced PGI(2) release ( approximately 45% at 1 microM) but did not significantly modify early MAPK activation or Cox-2 expression. Simvastatin alone did not significantly affect PGI(2) release. Our results suggest that mechanisms associated with G protein-coupled receptor activation, trigger Cox-2 up-regulation and PGI(2) release via multiple MAPK signalling pathways in VSMC. The mechanism is independent of tyrosine kinase receptors, although cytosolic tyrosine kinases could activate Cox-2 post-translationally. The potential contribution of HDL to vascular homeostasis, via increases in PGI(2) synthesis, could be enhanced by HMG-CoA reductase inhibitors.
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PMID:Simvastatin potenciates PGI(2) release induced by HDL in human VSMC: effect on Cox-2 up-regulation and MAPK signalling pathways activated by HDL. 1513 60

To understand the role of prostacyclin (PGI(2)) in protecting endothelial cells from apoptosis, we evaluated the effects of carbaprostacyclin (cPGI(2)) on H(2)O(2)-induced human umbilical vein endothelial cell (HUVEC) apoptosis. cPGI(2) suppressed H(2)O(2)-induced annexin V-positive cells in a concentration- and time-dependent manner. Pre-treatment of HUVEC with 50 microM cPGI(2) for 4 h produced the maximal anti-apoptotic effect. Authentic PGI(2) generated by adenoviral transfer of PGI(2) synthetic genes exerted a similar protective effect. cPGI(2) inhibited Smac/DIABLO release from mitochondria, caspase 3 activation, focal adhesion protein degradation, and cell detachment. cPGI(2) selectively protected X-linked inhibitor of apoptosis protein (X-linked IAP, XIAP) from H(2)O(2)-induced ubiquitination, and preserved XIAP protein levels. PD-98059 but not H-89 abrogated the protective action of cPGI(2). cPGI(2) increased ERK phosphorylation which was blocked by PD-98059. HUVEC stably transfected with dominant negative Ras abrogated XIAP preservation by cPGI(2) while constitutive active Ras increased ERK phosphorylation and protected XIAP from degradation. Our results demonstrate for the first time that PGI(2) inhibits XIAP ubiquitination and degradation via the Ras/MEK-1/ERK signaling pathway. Preservation of XIAP proteins represents a key mechanism by which PGI(2) protects endothelial cells from oxidant-induced apoptosis.
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PMID:Prostacyclin inhibits endothelial cell XIAP ubiquitination and degradation. 1745 May 18

Fibroblasts release prostaglandins and express a range of prostanoid receptors. However the importance of prostaglandins in fibroblast biology have not been fully explored. Our studies showed that the prostaglandin metabolite PGI(2) blocks the activation of fibroblasts, antagonising the induction of Ras/MEK/ERK signalling by TGFbeta. Endogenous PGI(2) acts so as to limit the activation of fibroblasts following tissue injury. By contrast PGE(2) induced in injured tissues or disease states may promote recruitment of inflammatory cells and lead to secondary activation of fibroblasts. The effects of PGI(2) on cell signaling could be manipulated to inhibit fibrosis in patients.
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PMID:Role of prostaglandins in fibroblast activation and fibrosis. 2053 82

Accumulating evidence suggests that sphingosine kinase 1 (SphK1) plays a key role in carcinogenesis by regulating cyclooxygenase-2 (COX-2) expression. Recent clinical studies have revealed that COX-2 inhibitors cause adverse cardiovascular side effects, likely due to inhibition of prostacyclin (PGI(2)). In this work, we investigated the roles of SphK1 inhibition on blood pressure (BP). The results show that lack of SphK1 expression did not exacerbate angiotensin II (Ang II)-induced acute hypertension, whereas celecoxib, a COX-2 inhibitor, augmented and sustained higher BP in mice. Interestingly, SphK1-knockout mice inhibited prostaglandin E(2) (PGE(2)) but not PGI(2) production in response to Ang II, whereas celecoxib blocked both PGE(2) and PGI(2) production. Mechanistically, SphK1 down-regulation by siRNA in human umbilical vein endothelial cells decreased cytokine-induced PGE(2) production primarily through inhibition of microsomal PGE synthase-1 (mPGES-1), not COX-2. SphK1 down-regulation also decreased MKK6 expression, which phosphorylates and activates P38 MAPK, which, in turn, regulates early growth response-1 (Egr-1), a transcription factor of mPGES-1. Together, these data indicate that SphK1 regulates PGE(2) production by mPGES-1 expression via the p38 MAPK pathway, independent of COX-2 signaling, in endothelial cells, suggesting that SphK1 inhibition may be a promising strategy for cancer chemoprevention with lack of the adverse cardiovascular side effects associated with coxibs.
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PMID:Effect of sphingosine kinase 1 inhibition on blood pressure. 2310 73


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