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:2.7.11.13 (protein kinase C)
49,245 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The effect of endothelin-1(ET-1) on pulmonary surfactant(PS) synthesis was studied in cultured lung explants without serum. The results showed that: 1. ET-1 increased [3H] choline incorporation with dose-dependence and time-dependence. 10(-10) mol.L-1 ET-1 increased the contents of total phospholipids, phosphatidylcholine and phosphatidylglcerol in lung tissues. The major membrane characteristic phospholipids, such as phosphatidylethanolamine, phosphatidylinostitol, phosphatidylserine and sphingomyelin, did not show changes. 2. BQ123, a ETA receptor selective antagonist, could decline the [3H] choline incorporation induced by ET-1(10(-12) and 10(-10) mol.L-1) (P < 0.01). 3. PMA, a protein kinase C(PKC) activator, increased [3H] choline incorporation into lung tissues (P < 0.01); the PKC inhibitor H7 decreased [3H] choline incorporation induced by ET-1(P < 0.01). The results demonstrated that ET-1 at physiological level can enhance the PS synthesis mediated by ETA receptor and PKC.
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PMID:[Modulation of endothelin-1 on pulmonary surfactant synthesis in lung explants]. 1080 58

Endothelins (ETs) are a family of 21-amino acid hypertensive peptides, which together with their receptors ETA and ETB are expressed in human adrenal cortex. Evidence has been provided that ETs exert a potent secretagogue effect on human adrenocortical cells, acting through both ETA and ETB receptors. Therefore, it seemed worthwhile to study the signaling cascades mediating the cortisol secretagogue effect of the two receptor subtypes. Normal adrenal glands were obtained from consenting patients undergoing unilateral nephrectomy with ipsilateral adrenalectomy for renal cancer. Dispersed zona fasciculata-reticularis (ZF/R) cells were obtained by collagenase digestion and mechanical disaggregation. The selective activation of ETA and ETB receptors was obtained by exposing dispersed cells to ET-1 plus the ETB receptor antagonist BQ-788 and to the selective ETB receptor agonist BQ-3020, respectively. ETA and ETB receptors about equally contributed to the cortisol response of dispersed ZF/R cells to ETs. The phospholipase (PL) C inhibitor U-73122 abolished ETA-mediated secretory response, but only partially prevented the ETB-mediated one. The phosphatidylinositol 3-kinase inhibitor wortmannin and the protein kinase (PK) C inhibitor calphostin-C significantly blunted the secretory responses ensuing from the activation of both receptor subtypes, while the Ca(2+)-channel blocker nifedipine was ineffective. The ETB receptor-, but not the ETA receptor-mediated cortisol response was partially reversed by the cyclooxygenase (COX) inhibitor indomethacin, which when added together with U-73122 abolished it. The inhibitors of adenylate cyclase, PKA, tyrosine kinase and lipoxygenase did not affect the secretory response to the activation of either receptor subtype. ETA-receptor activation raised inositol triphosphate (IP3) production from dispersed ZF/R cells, while ETB-receptor stimulation enhanced both IP3 and prostaglandin-E(2) production. Collectively, our findings indicate that ETs stimulate cortisol secretion from human ZF/R cells, acting through ETA receptors exclusively coupled with PLC/PKC-dependent pathway and ETB receptors coupled with both PLC/PKC- and COX-dependent cascades.
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PMID:Signaling pathways involved in the A and B receptor-mediated cortisol secretagogue effect of endothelins in the human adrenal cortex. 1117 11

This study examines endothelin-induced modulation of extracellular matrix synthesis and remodeling by fibroblasts, and its potential role in the pathogenesis of systemic sclerosis (scleroderma). Endothelin-1 promoted fibroblast synthesis of collagen types I and III, but not fibronectin, by a mechanism dependent upon both ETA and ETB receptors. Conversely, endothelin-1 inhibited both protein expression of matrix metalloproteinase 1 and zymographic activity exclusively via ETA receptors. A dual regulatory role for endothelin-1 in transcriptional regulation was suggested by the ability of endothelin-1 to enhance steady-state levels of collagen mRNA and activate the proalpha2(I) collagen (Col1a2) promoter, but in contrast to reduce matrix metalloproteinase 1 transcript expression and suppress transcription of a human matrix metalloproteinase 1 promoter reporter construct in transient transfection assays. Although endothelin-1 significantly enhanced remodeling of three-dimensional collagen lattices populated by normal fibroblasts, this was not observed for lattices populated by systemic sclerosis fibroblasts. Promotion of matrix remodeling was dependent upon ETA receptor expression and was blocked by specific inhibitors of tyrosine kinases or protein kinase C. Reverse transcriptase polymerase chain reaction, S1 nuclease, and functional cell surface binding studies showed that normal and systemic sclerosis fibroblasts express both ETA and ETB receptors (predominantly ETA), but that ETA receptor mRNA levels and ETA binding sites on fibroblasts cultured from systemic sclerosis skin biopsies are reduced by almost 50%. Endothelin-1 is thus able to induce a fibrogenic phenotype in normal fibroblasts that is similar to that of lesional systemic sclerosis fibroblasts. Moreover, reduced responsiveness to exogenous endothelin-1 in systemic sclerosis suggests that downstream pathways may have already been activated in vivo. These data further implicate dysregulated endothelin-receptor pathways in fibroblasts in the pathogenesis of connective tissue fibrosis.
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PMID:Fibroblast matrix gene expression and connective tissue remodeling: role of endothelin-1. 1123 16

This study investigated the role of nitric oxide(NO) in the prevention of myocardial hypertrophic response and its mechanisms. Left ventricular NO content decreases in the pathophysiogenesis of myocardial hypertrophy induced by pressure overload. Endogenous NO may attenuate cardiac hypertrophy induced by pressure overload, independent of cGMP mechanism. Angiotensin II (AII), endothelin-1 (ET-1) and norepinephrine(NE) can inhibit NOS activity and NO production, and induce hypertrophic response in cultured neonatal rat cardiomyocytes; these effects of AII, ET-1 and NE are mediated respectively by AII receptor, ETA receptor and alpha 1-adrenergic receptor; these effects of AII and ET-1 are mediated by PTX-sensitive G protein, while the effects of NE are mediated by PTX-insensitive G protein. eNOS gene is expressed in cultured neonatal rat cardiac myocytes and nonmyocytes. AII, ET-1 and NE can inhibit eNOS gene expression in cardiomyocytes. Exogenous NO can prevent hypertrophic response induced by AII, ET-1 and NE in cardiomyocytes. Both endogenous and exogenous NO can inhibit the expression of proto-oncogene c-fos induced by AII and ET-1, which may be involved in protein kinase C.
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PMID:[The role of nitric oxide in the prevention of myocardial hypertrophic response and its mechanisms]. 1137 22

The present work demonstrated that cultured neonatal rat ventricular fibroblast conditioned growth medium (FCGM) could significantly increase cell surface area and protein content and promote (3)H -Leucine incorporation on neonatal rat cardiomyocyte. The above effect was strongest on the third day, and was dose-dependent. BQ(123), an ET-A receptor antagonist, significantly blocked the effect, while CV11974, an Ang II I-type receptor antagonist, and regitin, an alpha-adrenergic receptor antagonist, did not. These results suggest that there are some substances promoting hypertrophy of cardiomyocytes in FCGM, which may be ET-1. The FCGM-induced increases in cardiomyocyte protein synthesis and cell surface area were inhibited partially by pertusis toxin (PTX) and PKC inhibitor staurosporine (ST), suggesting that the hypertrophic effect is related with PTX sensitive G protein and PKC.
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PMID:[Cardiocyte hypertrophy induced by cultured neonatal rat ventricular fibroblast conditioned growth medium]. 1197 Nov 68

The present study investigates whether endothelin-1 (ET-1), like noradrenaline (NA), stimulates the release of arachidonic acid (AA) via cytosolic phospholipase A2 (cPLA2) in rat tail artery. In tail artery segments labelled with [3H]AA, ET-1-induced AA release in a concentration-dependent manner with an EC50 of 1.3 nM. The effect of ET-1 was inhibited by bosentan and was insensitive to BQ788, suggesting the involvement of ETA receptor. The stimulation of AA release induced by ET-1 was prevented by arachydonyl trifluoromethyl ketone (AACOCF3), a selective inhibitor of cPLA2 and not by RHC80267, a diacylglycerol lipase inhibitor. Furthermore, PD98059, inhibitor of mitogen-activated protein kinase kinase (MEK) cascade and calphostin C, a protein kinase C (PKC) inhibitor, prevented the stimulation of AA release induced by ET-1 and NA. Immunoblotting of the cytosolic fraction of rat tail arteries stimulated with ET-1 or NA showed an increase in extracellular signal-regulated kinases (ERKs) phosphorylation and this effect was abolished by calphostin C treatment. These findings show that in rat tail artery ET-1 and NA induce a sequential activation of protein kinase C and extracellular signal-regulated kinases that results in stimulation of AA release via cPLA2 activation. This may represent a general pathway by which G-proteins coupled receptors stimulate AA release and its metabolites in vascular smooth muscle.
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PMID:Endothelin-1-induced arachidonic acid release by cytosolic phospholipase A2 activation in rat vascular smooth muscle via extracellular signal-regulated kinases pathway. 1214 93

The aims of this study were to investigate the effects of a selective ETA (BQ-123), a selective ETB (BQ-788), and a specific mixed ETA/ETB receptor antagonist (bosentan) on the pulmonary vasoconstriction induced by hypoxia in the isolated perfused rat lung, and the role of nitric oxide, adenosine triphosphate-sensitive (KATP), large conductance Ca+-activated (BKCa) and 4-aminopyridine-sensitive voltage-gated K channels (K+) in the relaxant effects of the selective ETA receptor antagonist BQ-123 and a protein kinase C inhibitor, bisindolylmaleimide I. K+ channels were inhibited by glibenclamide, charybdotoxin, and 4-aminopyridine and nitric oxide synthase by L-NG-nitroarginine methyl ester (L-NAME). Hypoxic ventilation produced a significant pressure response (+57%, p < 0.001). BQ-123, bosentan, and bisindolylmaleimide I induced a concentration-dependent decrease of the hypoxic pressure response (p < 0.001), whereas BQ-788 did not exhibit any inhibitory effect against hypoxic pressure response. Glibenclamide, charybdotoxin, and 4-aminopyridine partially opposed the inhibitory effects elicited by BQ-123 (p < 0.05), but L-NAME did not modify these effects. The effects of bisindolylmaleimide I on hypoxic pressure response were unaffected by glibenclamide, charybdotoxin, or 4-aminopyridine. The authors conclude that (a) ETA receptors and protein kinase C are involved in the modulation of hypoxic pulmonary vasoconstriction; and (b) the ETA antagonist BQ-123 opposes hypoxic pulmonary vasoconstriction through KATP, KV, and BKCa channels, differing in this from the protein kinase C inhibitor bisindolylmaleimide I. These results suggest that BQ-123 operates through a mechanism independent of bisindolylmaleimide I-inhibited protein kinase C isoforms.
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PMID:ETA, mixed ETA/ETB receptor antagonists, and protein kinase C inhibitor prevent acute hypoxic pulmonary vasoconstriction: influence of potassium channels. 1250 29

Apoptosis of cardiac myocytes is thought to be a feature of many pathological disorders, including congestive heart failure (CHF) and ischemic heart disease (IHD). Because recent investigations indicate that endothelin-1 (ET-1) plays an important role in CHF and IHD, we investigated the effect of ET-1 on cardiomyocyte apoptosis. The presence of apoptosis in rat cardiomyocytes (H9c2 and neonatal) was evaluated by morphological criteria, electrophoresis of DNA fragments, 4',6'-diamidine-2'-phenylindole staining, and TUNEL analysis. ET-1, but not angiotensin II, prevented apoptosis induced by serum deprivation via ETA receptors in a dose-dependent manner (1 to 100 nmol/L). ET-1 also prevented cytochrome c release from mitochondria to the cytosol. The use of specific pharmacological inhibitors demonstrated that the antiapoptotic effect of ET-1 was mediated through a tyrosine kinase pathway (genistein and AG490) but not through protein kinase C (PKC; calphostin C), mitogen-activated protein kinases (PD98059 and SB203580), or PKA (KT5270) pathways. Adenovirus-mediated gene transfer of kinase-inactive (KI) c-Src reversed the antiapoptotic effect of ET-1. We further investigated whether Bcl-xL, an antiapoptotic molecule, would be upregulated by using a luciferase-based reporter system. ET-1 upregulated Bcl-xL, and this upregulation was inhibited by genistein or AG490 but not by calphostin C. The experiments with KI mutants for various tyrosine kinases revealed that c-Src and Pyk2 (but not JAK1, Jak2, Syk, and Tec) are involved in ET-1-induced upregulation of Bcl-xL expression. These findings suggest that ET-1 prevents apoptosis in cardiac myocytes through the ETA receptor and the subsequent c-Src/Bcl-xL-dependent pathway.
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PMID:Antiapoptotic effect of endothelin-1 in rat cardiomyocytes in vitro. 1266 84

Ca+ sparks originating from ryanodine receptors (RyRs) are known to cause membrane hyperpolarization and vasorelaxation in systemic arterial myocytes. By contrast, we have found that Ca2+ sparks of pulmonary arterial smooth muscle cells (PASMCs) are associated with membrane depolarization and activated by endothelin-1 (ET-1), a potent vasoconstrictor that mediates/modulates acute and chronic hypoxic pulmonary vasoconstriction. In this study, we characterized the effects of ET-1 on the physical properties of Ca2+ sparks and probed the signal transduction mechanism for spark activation in rat intralobar PASMCs. Application of ET-1 at 0.1-10 nM caused concentration-dependent increases in frequency, duration, and amplitude of Ca2+ sparks. The ET-1-induced increase in spark frequency was inhibited by BQ-123, an ETA-receptor antagonist; by U-73122, a PLC inhibitor; and by xestospongin C and 2-aminoethyl diphenylborate, antagonists of inositol trisphosphate (IP3) receptors (IP3Rs). However, it was unrelated to sarcoplasmic reticulum Ca2+ content, activation of L-type Ca2+ channels, PKC, or cADP ribose. Photorelease of caged-IP3 indicated that Ca2+ release from IP3R could cross-activate RyRs to generate Ca2+ sparks. Immunocytochemistry showed that the distributions of IP3Rs and RyRs were similar in PASMCs. Moreover, inhibition of Ca2+ sparks with ryanodine caused a significant rightward shift in the ET-1 concentration-tension relationship in pulmonary arteries. These results suggest that ET-1 activation of Ca2+ sparks is mediated via the ETA receptor-PLC-IP3 pathway and local Ca2+ cross-signaling between IP3Rs and RyRs; in addition, this novel signaling mechanism contributes significantly to the ET-1-induced vasoconstriction in pulmonary arteries.
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PMID:ET-1 activates Ca2+ sparks in PASMC: local Ca2+ signaling between inositol trisphosphate and ryanodine receptors. 1274 Feb 15

1. Endothelin-1 (ET-1) and tumor necrosis factor alpha (TNFalpha) by their action on adipocytes have been independently linked to the pathogenesis of insulino-resistance. In isolated adipocytes, TNFalpha induces the expression of the inducible nitric oxide synthase (iNOS). The purpose of the present work was, in the 3T3-F442A adipocyte cell line, to characterise TNFalpha-induced iNOS expression and to determine whether or not ET-1 could influence TNFalpha-induced iNOS expression and NO production. 2. In differentiated 3T3-F442A, treatment with TNFalpha (20 ng ml(-1)) induced the expression of a functional iNOS as demonstrated by nitrite assay, Western blot, reverse transcription-polymerase chain reaction and Northern blot analysis. TNFalpha-induced iNOS expression requires nuclear factor kappaB activation, but does not necessitate the activation of the PI-3 kinase/Akt and P38-MAP kinase pathways. 3. ET-1, but not ET-3, inhibited the TNFalpha-induced expression of iNOS protein and mRNA as well as nitrite production. The effects of ET-1 were blocked by a specific ETA (BQ123, pA(2) 7.4) but not by a specific ETB receptor antagonist (BQ788). 3T3-F442A adipocytes express the mRNAs for prepro-ET-1 and the ET-A receptor subtype, but not for the ET-B subtype. 4. The inhibitory effect of ET-1 was not affected by bisindolylmaleimide, SB 203580 or indomethacin, inhibitors of protein kinase C, p38-MAP kinase and cyclooxygenase, respectively, and was not associated with cAMP production. However, the effect of ET-1 was partially reversed by wortmannin, suggesting the involvement of PI3 kinase in the transduction signal of ET-1. 5. Differentiated 3T3-F442A adipocytes did not release ET-1 with or without exposure to TNFalpha, although the mRNA for preproET-1 was detected in both pre- and differentiated adipocytes. 6. Thus, these results confirm that adipocytes are a target for circulating ET-1 and demonstrate that the activation of the ETA receptor subtype can prevent TNFalpha-induced iNOS expression.
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PMID:Endothelin-1 inhibits TNF alpha-induced iNOS expression in 3T3-F442A adipocytes. 1283 67


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