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:2.7.10.1 (ERK)
95,504 document(s) hit in 31,850,051 MEDLINE articles (0.01 seconds)

Low physiological concentrations of 17beta-estradiol increased the intracellular pH of rat aortic smooth muscle cells by a rapid nongenomic mechanism. This effect was due to stimulation of the Na+/H+ exchanger activity, measured using the intracellular pH-sensitive fluorescent probe 2',7'-bis-(2-carboxyethyl)-5-(and-6)-carboxyfluorescein. The 17beta-estradiol gave rise to a bell-shaped dose response, with a maximum at 10-12 m and no significant effect at 10-9 m. The specificity of the effect was verified by the use of the Na+/H+ exchanger inhibitor 5-(ethyl-N-isopropyl)amiloride and the lack of effect of the isomer 17alpha-estradiol. Inhibitors of the nuclear estrogen receptors, tamoxifen and ICI 182,780, completely prevented activation of the exchanger by 17beta-estradiol. The effect of low estrogen concentrations on the intracellular pH was mimicked by both norepinephrine and phenylephrine, suggesting a connection between the increase of intracellular pH and the muscle contraction process. The transduction mechanism for this nongenomic effect of estrogens did not involve modulation of the cAMP content, whereas inositol 1,4,5-trisphosphate, protein kinase C and MAPK pathways appear to play a role, as indicated by both pharmacological approaches and immunoblot experiments on protein kinase C translocation and ERK phosphorylation. These results for the first time provide evidence for a nongenomic effect of low physiological concentrations of 17beta-estradiol on intracellular pH that, together with other factors, may contribute to the development of hypertension and atherosclerosis in men and postmenopausal women and increase the risk of cardiovascular disease. Paradoxically, the lack of stimulation at high physiological estradiol levels could explain the protective effects found in premenopausal women.
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PMID:Short-term activation by low 17beta-estradiol concentrations of the Na+/H+ exchanger in rat aortic smooth muscle cells: physiopathological implications. 1295 86

Flavonoids isolated from cocoa have biological activities relevant to oxidant defenses, vascular health, tumor suppression, and immune function. The intake of certain dietary flavonoids, along with other dietary substances such as tocopherols, ascorbate, and carotenoids, is epidemiologically associated with a reduced risk of cardiovascular disease. Flavonoids have also been shown to modulate tumor pathology in vitro and in animal models. We took advantage of the conserved sequences found in tyrosine kinases to study the influence of cocoa fractions and controls on gene expression. We report that the pentameric procyanidin (molecular weight of 1442 daltons) fraction isolated from cocoa was a potent inhibitor of tyrosine kinase ErbB2 expression, a receptor important in angiogenesis regulation. Consistent with this primary observation, the cocoa flavonoid fraction also suppressed human aortic endothelial cell (HAEC) growth and decreased expression of two tyrosine kinases responsive to ErbB2 modulation, namely VEGFR-2/KDR and MapK 11/p38beta2. These inhibitory effects were observed when HAECs were treated with the flavonol fraction (molecular weight 280 daltons) isolated from cocoa, which comprise the structural subunits from which the procyanidin flavonoid subclass is biosynthetically constructed. Down-regulation of ErbB2 and inhibition of HAEC growth by cocoa procyanidins may have several downstream implications, including reduced vascular endothelial growth factor (VEGF) activity and angiogenic activity associated with tumor pathology. These results suggest specific dietary flavonoids are capable of selectively inhibiting ErbB2 and therefore may offer important insight into the design of therapeutic agents that target tumors overexpressing ErbB2.
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PMID:Pentameric procyanidins isolated from Theobroma cacao seeds selectively downregulate ErbB2 in human aortic endothelial cells. 1498 18

C-reactive protein (CRP) is significantly associated with the risk of ischemic cardiovascular disease in epidemiological studies. To explore if CRP has a functional role, we investigated its effect on the gene expression profile of vascular endothelial cells. Human vascular endothelial cells (human umbilical vein endothelial cells and human aortic endothelial cells) were incubated with CRP at various concentrations (0-10 mug/ml). Microarray analysis showed that a total of 11 genes increased (IL-8, core promoter element binding protein, activin A, monocyte chemoattractant protein 1, Exostoses 1, Cbp/p300-interacting transactivator with Glu/Asp-rich COOH-terminal domain 2, plasminogen activator inhibitor 1, fibronectin-1, gravin, connexin43, and sortilin-related receptor-1) and 6 genes decreased (methionine adenosyltransferase 2A, tryptophan-rich basic protein, reticulocalbin 1, membrane-associated RING-CH protein VI, cytoplasmic dynein1, and annexin A(1)) by more than twofold for their mRNA levels. IL-8 was the most significantly upregulated gene (13.6-fold), which demonstrated a clear dose- and time-dependent pattern revealed by quantitative real-time PCR. Cell adhesion assay showed that CRP enhanced the monocyte adhesion to endothelial cell monolayer by 2-fold (P < 0.01), which was partially blocked by an anti-IL-8 antibody (34.2% inhibition, P < 0.01). Inhibition of ERK MAPK pathway using U0126 prevented CRP-induced IL-8 upregulation, and Western blot analysis revealed a rapid activation of ERK1/2 after CRP stimulation. These data showed that CRP can significantly influence gene expressions in vascular endothelium. The CRP-responsive genes suggested that CRP may have a broad functional role in cell growth and differentiation, vascular remodeling and solid tumor development.
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PMID:Effect of C-reactive protein on gene expression in vascular endothelial cells. 1559 Oct 95

Phosphorylation of eIF4E is associated with increased activity of the translational machinery. Oxidative stress of resident vascular cells and macrophages potently enhances eIF4E phosphorylation. Oxidative stress activates numerous intracellular signaling pathways, including MAP-family kinase pathways and pathways leading to S6 kinase activation. The activation of MAP-family kinase pathways leads to the activation of Mnk and hence eIF4E phosphorylation, whereas the S6 kinase pathway is not involved, based on insensitivity to its inhibitors rapamycin and wortmannin. Ca-dependent pathways have been implicated in eIF4E phosphorylation, but the oxidative stress response pathway targeting eIF4E does not appear to require their participation. The results suggest that the potent activation of ERK and p38 protein kinases is sufficient to account for the enhanced eIF4E phosphorylation. Either is independently sufficient to effect the change, as neither PD098059 (Erk pathway inhibitor) nor SB202190 (p38 pathway inhibitor) alone can block the response, but when combined the response is almost completely abrogated. Mnk activation by oxidative stress leading to enhanced eIF4E phosphorylation may play a role in promoting stress-induced hyperproliferative diseases, such as smooth muscle cell proliferation and hypertrophy in cardiovascular disease, as the synthesis of several key regulators of cell growth has been shown to be held in check by moderation of eIF4E activity.
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PMID:Signal transduction pathways leading to increased eIF4E phosphorylation caused by oxidative stress. 1568 19

Apolipoprotein E (APOE) polymorphism plays an important role in lipid metabolism. Preliminary evidence suggests that APOE genotype appears to be a risk factor for not only cardiovascular disease, but also Alzheimer's disease and cancer. We screened the APOE genotype in 290 breast cancer patients and 232 non-cancer controls and determined the relationship between APOE gene polymorphism and breast cancer in Taiwan. We found risk for breast cancer was associated with the APOE genotype (xi(2) = 8.652, p = 0.013). Carriers of the epsilon4 allele were more common in breast cancer cases than carriers of epsilon3 allele (p = 0.004, OR = 1.786, 95% CI: 1.197-2.664). In addition, the epsilon4 allele is also associated with HER2/neu negative status in breast cancer patients (p = 0.006, OR = 0.277, 95% CI: 0.111-0.693). No significant associations between APOE genotype and tumor grade, TN classification, progesterone receptor, estrogen receptor, lymphatic invasion, or recurrence of breast cancer were in evidence. These results suggest that the APOE epsilon4 allele may be a risk factor for breast cancer and correlates with HER2/neu negative status.
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PMID:Influences of apolipoprotein E polymorphism on the risk for breast cancer and HER2/neu status in Taiwan. 1583 Jan 39

The mechanisms by which long-chain dietary polyunsaturated fatty acids (PUFAs) protect against cardiovascular disease are largely unknown. The present study determines the effects of eicosapentaenoic acid (EPA) and arachidonic acid (ARA) on the response of neonatal rat cardiomyocytes to simulated ischaemia (SI) and reperfusion (R). Myocytes isolated from 1-2 day old Wistar rat hearts were cultured with or without EPA or ARA and exposed to 1 h SI followed by 30 minutes reperfusion. Apoptosis was evaluated by caspase-3 activation, poly-(ADP-ribose) polymerase (PARP) cleavage and nuclear condensation. EPA (20microM) and ARA (20microM) significantly inhibited caspase-3 activation and PARP-cleavage and reduced the apoptotic index during reperfusion. Both fatty acids significantly increased ERK phosphorylation and decreased p38 phosphorylation during reperfusion. The mechanism of action of ARA on the MAPKs was further investigated with okadaic acid (to inhibit serine-threonine phosphatases) and orthovanadate (to inhibit tyrosine phosphatases). Vanadate, but not okadaic acid, significantly reduced ARA-induced inhibition of p38 phosphorylation, suggesting the involvement a tyrosine phosphatase during SI/R. Mitogen-activated protein kinase phosphatase-1 (MKP-1), a dual-specificity phosphatase, was targeted and a significant induction of MKP-1 by ARA and EPA was observed. It was demonstrated for the first time that EPA and ARA protect neonatal cardiac myocytes from ischaemia/reperfusion-induced apoptosis through activation of ERK as well as induction of a dual-specific phosphatase, causing dephosphorylation of the pro-apoptotic kinase, p38. The cardioprotective effects of EPA and ARA could also be demonstrated on the functional recovery of isolated perfused hearts subjected to global ischemia.
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PMID:Long-chain polyunsaturated fatty acids protect the heart against ischemia/reperfusion-induced injury via a MAPK dependent pathway. 1621 66

Pathway specific resistance to insulin signaling through PI 3-kinase/Akt/eNOS associated with a normal or hyper-activated MAP kinase signaling in vascular tissues has recently been proposed as a candidate link between cardiovascular disease and insulin resistance. Growth stimulatory pathways other than ERK/MAP kinase, such as JAK/STAT have not yet been investigated in vessels of animal models of insulin resistance. Here we have examined whether insulin is able to activate JAK2/STAT pathway in rat aorta and also the regulation of this pathway in an animal model of obesity/insulin resistance. Our results demonstrate that insulin activates JAK2 tyrosine kinase activity in rat aorta in parallel with the activation of STAT3 and STAT5a/b. Moreover, it is shown that, in obese animals, JAK2/STAT and MAP kinase pathways are hyper-activated in response to insulin, which occurs in association with a reduced activation of PI 3-kinase/Akt pathway in aorta. The results of the present study suggest that, besides ERK/MAP kinase pathway, another potentially pro-atherogenic pathway, JAK2/STAT is hyper-activated in vessels in a state of insulin resistance and this phenomenon, in association with the inhibition of the PI 3-kinase/Akt pathway, may play an important role in the pathogenesis of cardiovascular diseases.
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PMID:Effect of obesity on insulin signaling through JAK2 in rat aorta. 1623 56

Modulation of Ca(2+)-activated K(+) channels (K(Ca)) has been implicated in the control of proliferation in vascular smooth muscle cells (VSMC) and other cell types. In the present study, we investigated the underlying signal transduction mechanisms leading to mitogen-induced alterations in the expression pattern of intermediate-conductance K(Ca) in VSMC. Regulation of expression of IK(Ca)/rK(Ca)3.1 and BK(Ca)/rK(Ca)1.1 in A7r5 cells, a cell line derived from rat aortic VSMC, was investigated by patch-clamp technique, quantitative RT-PCR, immunoblotting procedures, and siRNA strategy.PDGF stimulation for 2 and 48 h induced an 11- and 3.5-fold increase in rK(Ca)3.1 transcript levels resulting in a four- and seven-fold increase in IK(Ca) currents after 4 and 48 h, respectively. Upregulation of rK(Ca)3.1 transcript levels and channel function required phosphorylation of extracellular signal-regulated kinases (ERK1/2) and Ca(2+) mobilization, but not activation of p38-MAP kinase, c-Jun NH(2)-terminal kinase, protein kinase C, calcium-calmodulin kinase II and Src kinases. In contrast to rK(Ca)3.1, mRNA expression and functions of BK(Ca)/rK(Ca)1.1 were decreased by half following mitogenic stimulation. Downregulation of rK(Ca)1.1 did not require ERK1/2 phosphorylation or Ca(2+) mobilization. In an in vitro-proliferation assay, knockdown of rK(Ca)3.1 expression by siRNA completely abolished functional IK(Ca) channels and mitogenesis. Mitogen-induced upregulation of rK(Ca)3.1 expression is mediated via activation of the Raf/MEK- and ERK-signaling cascade in a Ca(2+)-dependent manner. Upregulation of rK(Ca)3.1 promotes VSMC proliferation and may thus represent a pharmacological target in cardiovascular disease states characterized by abnormal cell proliferation.
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PMID:Mitogenic modulation of Ca2+ -activated K+ channels in proliferating A7r5 vascular smooth muscle cells. 1677 Mar 24

In endothelial cells (EC), celecoxib inhibits expression of tissue factor (TF), a key protein for initiation and propagation of thrombus formation. The current study was designed to examine the effect of celecoxib on TF expression and activity in VSMC. In contrast to EC, celecoxib increased TNF-alpha-induced TF expression and surface activity in VSMC by 33% and 20%, respectively, as compared to TNF-alpha alone, while rofecoxib or NS-398 had no effect. Celecoxib increased p38 MAP kinase (p38), p44/42 MAP kinase (ERK), and p70S6 kinase (p70S6K) phosphorylation while leaving JNK activation unaffected. Simultaneous inhibition of p38 and ERK reduced TNF-alpha-induced TF expression by 59%, while inhibition of JNK with SP600125 did not affect TF expression. Thus, in contrast to endothelial cells, celecoxib does not inhibit TF expression in VSMC, but instead enhances it. As neither rofecoxib nor NS-398 affected TF expression, this effect does not seem to be related to COX-2 inhibition but rather appears to be mediated by an increase in p38, ERK, and p70S6K activation. The observation that the inhibiting effect of celecoxib on endothelial TF expression does not extend to VSMC may have important implications for patients with cardiovascular disease.
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PMID:Differential effect of celecoxib on tissue factor expression in human endothelial and vascular smooth muscle cells. 1694 34

Reconstituted high-density lipoprotein (rHDL) has been shown to produce a rapid regression of atherosclerosis in animal models and humans. Sphingosine-1-phosphate (S1P), which is a bioactive lipid in HDL, plays a role in mitogenesis, endothelial cell motility, and cell survival, as well as organization and differentiation into a vessel. In this study, we examined the direct role of a newly developed rHDL, [POPC(1-palmitoyl-2-oleoyl phosphatidylcholine)/S1P/apolipoproteinA-I(A-I)]rHDL containing S1P in tube formation in endothelial cells (ECs) as well as cholesterol efflux in macrophage. The effect of (POPC/S1P/A-I)rHDL on cholesterol efflux in macrophage was similar to that of conventional rHDL, (POPC/A-I)rHDL. In addition, (POPC/S1P/A-I)rHDL induced EC proliferation through the activation of phospho-Akt and phospho-extracellular-signal-regulated kinases (p-ERK) 1/2 and EC tube formation, and this effect was blocked by inhibitors of Akt, ERK and endothelial nitric-oxide synthase (eNOS). In addition, (POPC/S1P/A-I)rHDL-induced p-ERK1/2 activation and EC tube formation can be mainly attributed to S1P-stimulated signaling through S1P2 and S1P3 as determined by an anti-sense strategy. In conclusion, (POPC/S1P/A-I)rHDL induces cholesterol efflux independently of S1P but has additional S1P-mediated effects on EC tube formation mediated by Akt/ERK/NO through S1P2 and S1P3. In the future, these new discs may be useful for the treatment of atherosclerotic and ischemic cardiovascular disease, such as acute coronary syndrome and atherosclerosis obliterans.
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PMID:Newly developed reconstituted high-density lipoprotein containing sphingosine-1-phosphate induces endothelial tube formation. 1711 70


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