Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.13 (protein kinase C)
 49,245 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The link between endothelial nitric oxide synthase (eNOS) activation and vascular diameter during ischemia-reperfusion was investigated in the rat heart. After short (<30 min) and long (>45 min) time of ischemia conferred by coronary artery occlusion of the rats, reperfusion caused dilatation and constriction of arterioles, respectively. Partial oxygen pressure (pO2) measurement of the heart by the electrode confirmed the hyper-perfusion and no-reflow phenomena during reperfusion, as well as myocardial ischemia. The vascular diameter was correlated with phosphorylation of Akt and serine 1177 residue of eNOS, and formation of NO-bound guanylate cyclase (GC) by immuoflorescence study. Western blotting confirmed the phosphorylation of eNOS-Ser1177 depending on ischemia time. The constriction during reperfusion after 45 min of ischemia is supposedly caused by the inhibition of Akt-mediated eNOS-Ser1177 phosphorylation, which was suppressed by a PKC inhibitor chelerythrine, or ROS scavengers N-2-mercaptopropionyl glycine (MPG) and 4,5-Dihydroxy-1, 3-benzenedisulfonic acid disodium salt (Tiron). However, an endothelin receptor antagonist BQ123 alleviated the vasoconstriction by increasing NO availability but not eNOS-Ser1177 phosphorylation. Thus, vascular patency is correlated with eNOS-Ser1177 phosphorylation in association with ROS, and PKC during reperfusion. Endothelin inhibits vasodilatation by reducing NO availability during reperfusion.
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PMID:Endothelial NO Synthase (eNOS) phosphorylation regulates coronary diameter during ischemia-reperfusion in association with oxidative stress. 1603 23

Hemodynamic changes, including increased vasoconstriction and reduced blood flow have been detected in both human diabetic patients and in animal models of diabetes. We previously demonstrated that the endothelin (ET) system was upregulated and involved in mediating the exaggerated vasoconstrictor responses in superior mesenteric artery (SMA) from diabetic rats. Chronic treatment of diabetic rats with the dual endothelin receptor antagonist, bosentan abolished the enhanced contractile responses in diabetic SMA. The biological actions of ET-1 have been shown to be coupled to the hydrolysis of phosphotidylinositol 4,5-biphosphate and phosphotidylcholine and the subsequent production of diacylglycerol (DAG). DAG is an activator of the classical and novel isoforms of PKC. Increases in PKC activity, associated with translocation of specific PKC isoforms from the cytosol to the membrane, have been implicated in the vasoconstrictor effect of ET-1. The goal of the present study was to determine whether chronic treatment of diabetic rats with bosentan influences the activation of specific PKC isoforms in SMA from diabetic rats. Elevated levels of PKCbeta2 in both the cytosol and membrane fractions and PKCepsilon in the membrane fraction were detected in SMA from diabetic rats. However, neither the levels nor the distribution between the cytosol and membrane fractions of any of these PKC isoforms were affected by the treatment of the diabetic rats with bosentan. These observations indicate that bosentan improves vascular reactivity in STZ-diabetic rats by mechanisms other than correction of increased activities of PKC isoforms.
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PMID:Effect of chronic endothelin blockade on PKC isoform distribution in mesenteric arteries from diabetic rats. 1631 6

Adiponectin, which is specifically and highly expressed in adipose tissue, has pleiotropic insulin-sensitizing effects. Endothelin-1 (ET-1) is a potent vasoconstrictive peptide mainly produced by endothelial cells. We previously showed that ET-1 can induce insulin resistance in vitro and in vivo and proposed that it might regulate adiponectin expression and secretion, thus affecting the homeostasis of whole-body energy metabolism. In the present study, we explored the regulatory effects of ET-1 on adiponectin expression and secretion and the underlying mechanisms in 3T3-L1 adipocytes using Northern blotting and ELISA. ET-1 was found to cause a significant time- and dose-dependent decrease in adiponectin expression, and this effect was inhibited by the ET type A receptor (ETAR) antagonist BQ-610 but not by the ETBR antagonist BQ-788. To explore the underlying mechanism, we examined the involvement of the cAMP-dependent protein kinase A-, phospholipase A2-, protein kinase C-, and MAPK-mediated pathways using inhibitors and found that only PD98059 and U0126, inhibitors that blocked MAPK/ERK kinase's ability to activate the ERKs, prevented ET-1-induced down-regulation of adiponectin. Furthermore, acute ET-1 treatment significantly stimulated adiponectin secretion by 3T3-L1 adipocytes, and this effect was inhibited by the ETAR antagonist BQ-610, the inositol-1,4,5-triphosphate receptor blocker 2-APB, and phospholipase C inhibitor U73122, showing that the release of adiponectin stimulated by ET-1 was mediated through the ETAR and the inositol-1,4,5-triphosphate pathway. In conclusion, ET-1 regulates adiponectin expression and secretion by two different signaling pathways in 3T3-L1 adipocytes. These findings suggested that the cardiovascular system affects adipocyte physiology by regulating the expression of adipocytokines and, consequently, energy homeostasis via vasoactive factors, such as ET-1.
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PMID:Endothelin-1 regulates adiponectin gene expression and secretion in 3T3-L1 adipocytes via distinct signaling pathways. 1719 42

To study the role of endothelial factors in luteal function, the dynamic profiles of genes for endothelin 1 (EDN1), its receptor subtypes, EDNRA and EDNRB, and angiotensin converting enzyme (ACE) were examined in corpora lutea (CL) obtained from rabbits on Days 4 and 9 of pseudopregnancy after prostaglandin (PG) F2alpha analogue (alfaprostol) treatment. The cell type distribution of EDN1 in the ovaries and its mechanisms of actions in vitro and in vivo were also studied. Positive immunostaining for EDN1 was localized in the luteal and endothelial cells, in granulosa cells of the follicles, and in the ovarian epithelium. The basal mRNA levels for EDNRA, EDNRB, and ACE were lower (P </= 0.01) in Day-4 CL than in Day-9 CL, whereas those for EDN1 did not differ between these two time-points. On Day 4, the luteal EDN1, EDNRA, EDNRB, and ACE mRNA levels were similarly increased two-fold (P </= 0.01) 1.5 h after alfaprostol injection, and did not show further changes in the subsequent 24 h. On Day 9, alfaprostol challenge transiently up-regulated (P </= 0.01) the luteal ACE transcripts at 1.5 h, and those of EDN1 at 1.5 h and 3 h, whereas the EDNRA and EDNRB transcript levels remained unchanged during the course of luteal regression. EDN1 decreased (P </= 0.01) progesterone release and increased (P </= 0.01) PGF2alpha secretion and NOS activity via the PLC/PKC pathway in Day-9 CL, but not in Day-4 CL, cultured in vitro. EDN1-induced, but not alfaprostol-induced luteolysis, was blocked by cotreatment in vivo with the ACE antagonist captopril. These findings support the hypothesis that PGF2alpha regulates luteolysis through intraluteal activation of the renin-angiotensin/EDN1 systems in CL that have acquired luteolytic competence.
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PMID:Vasoactive peptides in the luteolytic process activated by PGF2alpha in pseudopregnant rabbits at different luteal stages. 1736 Sep 61

We have previously shown that endothelin-B receptor stimulation increases neural progenitor proliferation, partly in G(i) and extracellular matrix molecule-dependent manner. In the present study, we investigated whether G(q/11) is also involved in this response and how G(i) and G(q/11) might regulate the extracellular signal-regulated kinase (ERK) pathway and integrin signaling. Endothelin-induced ERK phosphorylation was independent of integrin ligands, and an inhibitor of G(q/11), YM-254890, as well as pertussis toxin, partially inhibited endothelin-stimulated phosphorylation of Raf-1 and ERK. Endothelin-stimulated protein kinase C (PKC) was partially inhibited by both YM-254890 and pertussis toxin, while only pertussis toxin attenuated endothelin-induced Ras activation. In contrast, endothelin increased tyrosine phosphorylation of focal adhesion kinase (FAK) and paxillin in an integrin ligand-dependent manner. Both YM-254890 and pertussis toxin partially inhibited endothelin-stimulated phosphorylation of these proteins. A PKC inhibitor and down-regulation of PKC prevented endothelin-induced phosphorylation of paxillin and ERK. In addition, endothelin-induced proliferation and DNA synthesis were partially inhibited by YM-254890 and pertussis toxin. Taken together, the results indicate that endothelin activates PKC via G(q/11) and G(i), and consequently stimulates the ERK cascade in cooperation with Ras signaling stimulated by G(i). PKC appears to increase tyrosine phosphorylation of paxillin to enhance integrin signaling, which further increases DNA synthesis and proliferation.
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PMID:Involvement of Gq/11 in both integrin signal-dependent and -independent pathways regulating endothelin-induced neural progenitor proliferation. 1770 40

Up-regulation of vascular endothelin type A (ET(A)) and type B (ET(B)) receptors are implicated in the pathogenesis of cardiovascular disease. Culture of arteries has been shown to induce similar receptor alterations and has therefore been suggested as a suitable method for in detail delineation of the regulation of endothelin receptors. We hypothesize that protein kinase C (PKC) and mitogen-activated kinases (MAPK) are involved in the regulation of endothelin receptors. Porcine coronary arteries were studied before and after 24 h of culture, using in vitro pharmacology, real-time PCR and immunofluorescence techniques. Sarafotoxin 6c and endothelin ET-1 were used to examine the endothelin ET(A) and ET(B) receptor effects. The involvement of PKC and MAPK in the receptor regulation was examined by culture in the presence of antagonists. Organ culture resulted in increased sarafotoxin 6c and endothelin-1 contractions, endothelin ET(A) and ET(B) receptor immunofluorescence staining intensities and endothelin ET(B), but not ET(A), receptor mRNA levels. The general PKC inhibitors, bisindolylmaleimide I (10 microM) or Ro-32-0432 (10 microM), inhibited these effects. Also, the increase in sarafotoxin 6c contraction, endothelin ET(B) receptor and mRNA levels and endothelin ET(A) and ET(B) immunofluorescence staining intensities were inhibited by MAPK inhibitors for extracellular signal related kinases 1 and 2 (ERK1/2), PD98059 (10 microM), C-jun terminal kinase (JNK), SP600125 (10 microM), but not by p38 MAPK, SB203580 (10 microM). In conclusion, PKC and MAPK seem to be involved in the regulation of endothelin receptor expression in porcine coronary arteries. Inhibiting these intracellular signal transduction pathways may provide a future therapeutic target for hindering the development of vascular endothelin receptor changes in cardiovascular disease.
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PMID:PKC and MAPK signalling pathways regulate vascular endothelin receptor expression. 1803 34

In vivo, endothelial cells are constantly exposed to shear stress by flowing blood. Short-term exposure of endothelial cells to shear stress has been shown to induce endothelin-1 release. It is currently unknown, however, whether this shear stress-dependent endothelin-1 release affects the expression and activity of transcription factors. In this study, primary cultures of human endothelial cells from the umbilical vein were exposed to laminar shear stress in a cone-and-plate viscometer. Laminar shear stress for 30 min induced a 2-fold increase in mRNA expression of c-jun , but not c-fos, in human endothelial cells. Blockade of endothelin receptor subtype B (ET B) with BQ788 prevented this shear stress-dependent induction of c-jun expression. The induction of c-jun by shear stress involved protein kinase C and endothelial NO synthase. In addition, exposure of endothelial cells to arterial laminar shear stress for 1 h increased the binding of transcription factor AP-1 to its consensus sequence by 1.7-fold in electrophoretic mobility shift assays. This induction was also mediated by an ET B-dependent pathway. Supershift analysis supports an AP-1 complex containing c-jun, but not c-fos, in human endothelial cells. In conclusion, our data suggest endothelin-1-mediated induction of c-jun expression and activation of AP-1 (possibly as a c-jun homodimer) by laminar shear stress in human endothelial cells.
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PMID:Endothelin receptor B-mediated induction of c-jun and AP-1 in response to shear stress in human endothelial cells. 1875 96

p120-catenin (p120) is required for cadherin stability and is thought to have a central role in modulating cell-cell adhesion. Several lines of evidence suggest that S/T phosphorylation may regulate p120 activity, but the upstream kinases involved have not been established, nor has a discreet measurable function been assigned to an individual site. To approach these issues, we have generated p120 phospho-specific monoclonal antibodies to several individual phosphorylation sites and are using them to pinpoint upstream kinases and signaling pathways that control p120 activity. Protein Kinase C (PKC) has been implicated as a signaling intermediate in several cadherin-associated cellular activities. Signaling events that activate PKC induce rapid phosphorylation at p120 Serine 879 (S879), suggesting that p120 activity is regulated, in part, by one or more PKC isoforms. Here, we find that physiologic activation of a G-protein coupled receptor (i.e., endothelin receptor), as well as several Receptor Tyrosine Kinases, induce rapid and robust p120 phosphorylation at S879, suggesting that these pathways crosstalk to cadherin complexes via p120. Using Va2 cells and PDGF stimulation, we show for the first time that PDGFR-mediated phosphorylation at this site is dependent on PKCalpha, a conventional PKC isoform implicated previously in disruption of adherens junctions.
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PMID:PDGF receptor activation induces p120-catenin phosphorylation at serine 879 via a PKCalpha-dependent pathway. 1895 Jun 21

Stroke is a serious neurological disease and the third leading cause of death in the western world. In roughly 15 % of the cases, the cause is due to an intracranial haemorrhage, and the remaining 85 % represent ischemic strokes. Ischemic stroke is caused by the occlusion of a cerebral artery either by an embolus or by local thrombosis. Several studies have shown an involvement of the endothelin system in ischemic stroke. This review aims to examine the alterations of vascular endothelin receptor expression in ischemic stroke. Furthermore, studies of the intracellular signalling pathways leading to the enhanced expression of vascular endothelin receptors show that both protein kinase C (PKC) and mitogen activating protein kinase (MAPK) play important roles. The results from this work provide new perspectives on the pathophysiology of ischemic stroke, and give a possible explanation to the beneficial effects of treatment with PKC and MAPK inhibitors to limit the infarct volume.
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PMID:Cerebrovascular endothelin receptor upregulation in cerebral ischemia. 1914 37

Acquired resistance to protein kinase C (PKC) modulators may explain the failure of clinical trials in patients with cancer. Herein, we established a human colon cancer cell line resistant to PEP005, a drug that inhibits PKCalpha and activates PKCdelta. Colo205-R cells, selected by stepwise exposure to PEP005, were >300-fold more resistant to PEP005 than parental Colo205-S cells and were cross-resistant to phorbol 12-myristate 13-acetate, bryostatin, bistratene A, and staurosporine. No PKCalpha or PKCdelta mutation was detected in Colo205-S and Colo205-R cells. Changes in Colo205-R cells were reminiscent of the epithelial-to-mesenchymal transition (EMT) phenotype. Accordingly, Colo205-R cells were more invasive than Colo205-S in Matrigel assays and in mouse xenografts. We also found an increased mRNA expression of several EMT genes, such as those encoding for transforming growth factor-beta and vimentin, along with a decreased mRNA expression of genes involved in epithelial differentiation, such as CDH1 (E-cadherin), CLDN4 (claudin 4), S100A4, and MUC1, in Colo205-R compared with Colo205-S cells in vitro and in vivo. Interestingly, high expression of ET-1 was shown in Colo205-R cells and correlated with low sensitivity to PEP005 and staurosporine in a panel of 10 human cancer cell lines. Inhibition of the ET-1 receptor ETR-A with bosentan restored the antiproliferative effects of PEP005 in Colo205-R cells and decreased the invasive properties of this cell line. Exogenous exposure to ET-1 and silencing ET-1 expression using small interfering RNA modulated cell signaling in Colo205-S and Colo205-R. In summary, acquired resistance to PEP005 was associated with expression of EMT markers and activates the ET-1/ETR-A cell signaling.
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PMID:Epithelial-to-mesenchymal transition and resistance to ingenol 3-angelate, a novel protein kinase C modulator, in colon cancer cells. 1941 39


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