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: UMLS:C0043167 (pertussis)
19,595 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Endothelial cells actively regulate their environment by secreting humoral substances, including endothelin-1 and a variety of eicosanoids, that have local actions. To elucidate interactions among these local mediators, we measured release of cyclooxygenase and lipoxygenase pathway products of arachidonate metabolism by human aortic endothelial cells after incubation with endothelin-1. Supernatants were collected, extracted, and fractionated using high-performance liquid chromatography. Radioimmunoassays for eicosanoids were performed on the appropriate fractions. After endothelin stimulation, production of the prostacyclin metabolite 6-ketoprostaglandin F1 alpha (6-keto-PGF1 alpha), the thromboxane (Tx) metabolite TxB2, and prostaglandin E2 (PGE2) were increased (307 +/- 48, 320 +/- 91, and 315 +/- 74% of control, P < 0.05). Leukotriene B4 (LTB4) release was modestly increased (195 +/- 19% of control, P < 0.05). The release of 5-hydroxyeicosatetraenoic acid (5-HETE) was increased (300 +/- 57% of control, P < 0.05); production of 12-HETE and 15-HETE was unchanged. Production of eicosanoids peaked between 30 and 120 min. Preincubation with pertussis toxin prevented increased production of PGE2, LTB4, and 5-HETE after endothelin-1 stimulation; pretreatment with sphingosine had no effect. Interactions between endothelin and eicosanoids may be important components of the complex network that regulates vascular tone, coagulation, and inflammation at the local level.
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PMID:Eicosanoid production by human aortic endothelial cells in response to endothelin. 781 Jul 29

Thromboxane A2 (TXA2), the major cyclooxygenase (COX) product of arachidonic acid (AA), activates platelets and is a potent vasoconstrictor. The functional importance of this eicosanoid has been demonstrated in syndromes of acute coronary ischaemia. The cellular response to this agonist is tightly regulated. The liberation of AA from membrane phospholipids is conventionally thought to be the rate limiting step in TXA2 biosynthesis. However, the discovery of a second, highly regulated COX gene (COX-2) and the demonstration of product-based inactivation of COX and thromboxane synthase suggest a more complex regulation of TXA2 formation. TXA2 signalling is mediated by a G-protein linked receptor (PGH2/TXA2 receptor) which activates phospholipase C (PLC). Pharmacological studies suggest two distinct binding sites on platelets, but receptor heterogeneity has yet to be documented at a molecular level. The PGH2/TXA2 receptors are linked via a pertussis and cholera toxin-insensitive G-protein which has not been fully characterized, but is thought to belong to the Gq class of G-proteins. The diversity of G-protein alpha subunits, and growing evidence suggesting functional roles for the beta-gamma subunit, support a possible dual signalling mechanism of cellular activation. This may be of particular importance in regulating the response to eicosanoids with contrasting actions. A receptor for prostacyclin (PGI2) has not yet been cloned but biochemical studies suggest that it is linked to the activation of adenylate cyclase via Gs. At least three distinct prostaglandin E receptors have been identified. Desensitization of the cellular responses to the activation of TXA2, PGI2 and PGE receptors have been demonstrated and potential phosphorylation sites in their COOH terminal ends may be important in mediating this effect.
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PMID:Cellular activation by thromboxane A2 and other eicosanoids. 813 96

It has previously been shown that thrombin effects on endothelial cells can be mediated via G-proteins, which couple the thrombin receptor to several key physiological responses. As G-proteins are known targets of bacterial toxins, specific toxins were used to further characterize G-protein involvement in thrombin activation of bovine pulmonary arterial endothelial cells (BPAEC) and human umbilical vein endothelial cells (HUVEC). Homogenates were exposed to several bacterial toxins in the presence of 32P-NAD and ADP ribosylation of proteins determined by autoradiography of SDS-PAGE gels. Major substrates were a 40 kDa protein for pertussis toxin, 39, 45 and 52 kDa proteins (Gs) for cholera toxin, a 21 kDa protein for botulinum toxin C, and a 43 kDa protein (actin) for botulinum toxin C2a. The increase in either HUVEC or BPAEC PGI2 release induced by thrombin was not altered by pretreatment with any toxin. However, 1 h treatment of BPAEC monolayers with 1 microgram/ml pertussis toxin resulted in dramatic barrier dysfunction, which was synergistic with the albumin permeability induced by 1 microM thrombin. In contrast, pretreatment with 1 microgram/ml cholera toxin completely prevented the thrombin-induced barrier dysfunction. Moreover, contraction and gap formation due to thrombin challenge, observed by phase contrast microscopy, was greatly augmented by pertussis toxin and prevented by cholera toxin. Whereas 5 micrograms/ml botulinum toxin C did not affect either basal or thrombin-induced barrier dysfunction, botulinum toxin C2a increased basal BPAEC permeability over four-fold. Thus, bacterial toxins have specific and divergent effects on thrombin-induced endothelial cell responses. Botulinum toxin C2a appears to interact directly with actin to produce barrier dysfunction. In contrast, cholera toxin promotes barrier function via its known effects on Gs, stimulating adenylate cyclase and increasing cAMP. Because cholera toxin and pertussis toxin (via inhibition of G(i)) both increase cAMP, yet have opposing effects on barrier function, the present results suggest that pertussis toxin produces barrier dysfunction via ADP ribosylation of a novel G-protein other than G(i) or via a novel action of G(i).
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PMID:Regulation of thrombin-induced endothelial cell activation by bacterial toxins. 818 Mar 40

In cultured cells the cytopathic effects (CPE) of Clostridium difficile toxins A and B are superficially similar. The irreversible CPEs involve a reorganization of the cytoskeleton, but the molecular details of the mechanism(s) of action are unknown. As part of the work to elucidate the events leading to the CPE, cultured cells were preincubated with agents known to either stimulate or inhibit some major signal transduction pathways, whereupon toxin was added and the development of the CPE was followed. Both toxin-induced CPEs were enhanced by phorbol esters and mezerein, which stimulate protein kinase C, while they were inhibited by the phospholipase A2 inhibitors quinacrine and 4-bromophenacylbromide. Agents affecting certain G-proteins, cGMP and cAMP levels, phosphatases, prostacyclin, lipoxygenase, and phospholipase C did not affect the development of the CPE of either toxin. Thus, the cytoskeletal effect induced by toxins A or B appears to require PLA2 activity and involves at least part of a protein kinase C-dependent pathway, but not pertussis toxin-sensitive G-proteins, cyclic nucleotides, eicosanoid metabolites, or phospholipase C activity. In addition, both toxins were shown to activate phospholipase A2.
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PMID:Signal transduction pathways and cellular intoxication with Clostridium difficile toxins. 832 Feb 69

Interleukin-1 (IL-1) is a key inflammatory cytokine that has important effects both on endothelial cell (EC) growth and synthetic function. Fibroblast growth factors (FGF's), including endothelial cell growth factor (ECGF), are important regulators of EC growth, and their role in the pannus formation and synovial proliferation seen in chronic arthritis has been emphasized recently. While ECGF mediated EC proliferation is inhibited by IL-1, potential interaction of these peptides on other aspects of EC function has not been described. As both IL-1 and FGF may be important disease mediators in rheumatoid arthritis, we studied their combined effects on EC prostacyclin production. While ECGF alone had no measurable effects, it enhanced rIL-1 alpha induced prostacyclin production in a dose and time dependent fashion. Both pertussis and cholera toxins blocked the augmentation, suggesting a role for G proteins in mediating the synergism. These studies demonstrate that ECGF can alter certain effects of IL-1 on the endothelium, and point to an additional role that this family of growth factors may play in some inflammatory disorders.
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PMID:Augmentation of interleukin-1 induced prostacyclin production by endothelial cell growth factor: implications for chronic synovitis. 832 13

Treatment of cultured bovine carotid artery endothelial cells with 10(-7) M plasmin increased arachidonate release coupled with the increase in prostacyclin production. The stimulatory effect of plasmin on arachidonate release could be divided into the early and late phases according to its calcium dependency and pertussis toxin sensitivity. The early phase of plasmin-induced arachidonate release was a calcium-dependent and pertussis toxin-sensitive response, which was observed within 20 min after plasmin treatment. The late phase was a calcium-independent and pertussis toxin-insensitive response, which was induced gradually from 20 to 60 min. Induction of the early phase of plasmin's effect required both the lysine binding and catalytic sites in plasmin molecule because it was inhibited either by the binding antagonist tranexamic acid or by the serine protease inhibitor aprotinin. Guanosine 5'-O-(2-thiotriphosphate) potentiated the effect of plasmin in permeabilized or nonpermeabilized cells, indicating that the early phase effect was mediated by a pertussis toxin-sensitive guanosine 5'-triphosphate (GTP)-binding protein. The late phase of plasmin's effect was due to the catalytic activity because it was inhibited by aprotinin but not by tranexamic acid. Microplasmin structurally having the catalytic sites induced a similar late phase effect. Plasmin did not elicit the metabolism of phosphatidyl polyphosphoinositides. These studies demonstrate that the activation of phospholipase A2, which results in arachidonate release, in the early phase of plasmin's effect is a receptor-mediation via GTP-binding protein that is not coupled through phospholipase C activation.
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PMID:Human plasmin induces a receptor-mediated arachidonate release coupled with G proteins in endothelial cells. 838 26

Extracellular ATP plays an important role in the regulation of prostacyclin and nitric oxide release from vascular endothelial cells. These cellular responses to ATP are generally attributed to the stimulation of the P2y subtype of P2 purinergic receptors. However, it has recently been suggested that two types of ATP receptors might coexist on endothelial cells. To evaluate this hypothesis, we examined the effects of P2y receptor agonists 2-methylthioadenosine 5'-triphosphate (2MeSATP) and 2'- and 3'-O-(4-benzoylbenzoyl)adenosine 5'-triphosphate (BzATP) and of UTP on the accumulation of inositol phosphates in bovine aortic endothelial cells. BzATP, 2MeSATP, and UTP produced a smaller maximal effect than ATP. The effects of 2MeSATP and UTP were additive, whereas the effects of ATP and either UTP or 2MeSATP were not. Prior exposure to UTP reduced the subsequent response to UTP to 12% of the control response, whereas the response to 2MeSATP was decreased to 61%. Reciprocally, preincubation with 2MeSATP reduced the subsequent response to 2MeSATP to 23% of the control response, whereas the response to UTP was reduced to 73%. Pertussis toxin pretreatment decreased the response to both ATP and UTP (65% and 70% inhibition, respectively), whereas the response to 2MeSATP was not modified. Our data support the hypothesis that two classes of receptors recognizing ATP are expressed on bovine aortic endothelial cells.
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PMID:Heterogeneity of ATP receptors in aortic endothelial cells. Involvement of P2y and P2u receptors in inositol phosphate response. 843 80

NaF, a nonselective activator of heterotrimeric guanine nucleotide-binding proteins (G proteins), increased the release of arachidonic acid (AA) and prostacyclin (PGI2) production in bovine aortic endothelial cells (BAEC) at low concentrations (40-60 mM). On the other hand, higher concentrations (100 mM) inhibited phospholipase A2 (PLA2) compared with the basal activity. Intracellular Ca2+ levels did not rise after treatment with stimulatory concentrations of NaF, and, moreover, neither neomycin nor Ca(2+)-free medium affected the biphasic pattern of PGI2 synthesis in response to NaF. CGP-43187, an inhibitor of the 14-kDa secretory PLA2, did not affect NaF-induced AA release. However, AACOCF3, a specific inhibitor of the cytosolic 85-kDa PLA2 (cPLA2), abrogated AA release and PGI2 production in response to 60 mM NaF. A biphasic pattern of PGI2 production was also obtained with the guanosine 5'-triphosphate analogues guanosine 5'-O-(3-thiotriphosphate) and guanylylimidodiphosphate in permeabilized BAEC. Pretreatment of the cells with guanosine 5'-O-(2-thiodiphosphate) suppressed the inhibition and the stimulation of AA release induced by guanylylimidodiphosphate. In addition, phenylisopropyl adenosine inhibited the release of AA and PGI2, whereas ATP and bradykinin increased PGI2. Pertussis toxin not only inhibited ATP- and bradykinin-stimulated PGI2 release, it also reversed the inhibitory effect of phenylisopropyl adenosine, resulting in a significant stimulation. These findings strongly suggest that, in BAEC, cPLA2 is coupled with more than one G protein that are involved in inhibition and stimulation of cPLA2 activity.
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PMID:Dual regulation of PLA2 and PGI2 production by G proteins in bovine aortic endothelial cells. 876 95

The present study was conducted to localize and characterize the subtype(s) of muscarinic receptor involved in prostacyclin production elicited by the cholinergic transmitter acetylcholine (ACh) in various cell types in the rabbit heart. ACh increased prostacyclin synthesis, measured as 6-keto-prostaglandin(1 alpha) (6-keto-PGF(1 alpha)), in cultured coronary endothelial cells and freshly dissociated ventricular myocytes in a dose-dependent manner, but not in cultured coronary smooth muscle cells of rabbit heart. McN-A-343 {(4-hydroxy-2-butynyl)-1-trimethylammonium-m-chlorocarbanilate chloride}, a selective M1 muscarinic ACh receptor (mAChR) agonist, did not alter 6-keto-PGF(1 alpha) synthesis in these cell types. ACh induced 6-keto-PGF(1 alpha) synthesis in coronary endothelial cells and ventricular myocytes was not altered by a low concentration (0.01 microM) of pirenzepine, an M1 mAChR antagonist, but was reduced by a higher concentration (1 microM). In coronary endothelial cells, ACh-induced 6-keto-PGF(1 alpha) production was reduced by hexahydrosila-difendial (HHSiD), an M3 mAChR antagonist, and in ventricular myocytes by both AF-DX 116 [11-{2-[(diethylamino)methyl]-1-piperidinyl]acetyl-5,11-dihydro-6H- pyrido[2,3-b]-benzodiazepine-6 one}], an M2 receptor antagonist, and HHSiD. The decrease by ACh of isoproterenol-stimulated cAMP accumulation was minimized by AF-DX 116, but not by HHSiD or pirenzepine. Pertussis toxin treatment minimized ACh-induced decrease in isoproterenol-stimulated rise in cAMP, but not ACh-induced 6-keto-PGF(1 alpha) synthesis. These data suggest that ACh stimulates prostacyclin production in coronary endothelial cells via M3 mAChR and in ventricular myocytes via M2 and M3 mAChR, and may contribute to its cardioprotective effects. Moreover, ACh induced decrease in cAMP, but not the increase in 6-keto-PGF (1 alpha) production, is mediated by pertussis toxin-sensitive G(alpha i) proteins in these cells.
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PMID:Localization and characterization of the subtypes(s) of muscarinic receptor involved in prostacyclin synthesis in rabbit heart. 878 73

Ancrod-generated fibrin has been shown to stimulate prostacyclin synthesis of human umbilical vein endothelial cells (Chang et al., 1994, Biochem. Biophys. Res. Commun. 203, 1920). We further investigated its mechanism of action. The increment of 6-keto prostaglandin F1 alpha stimulated by ancrod-generated fibrin was almost completely inhibited when endothelial cells were either pretreated with 50 microM 8-(N,N'-diethylamino)octyl-3,4,5- trimethoxybenzoate (TMB-8) or preloaded with 15 microM 1,2-bis(2- aminophenoxy)ethane-N,N,N',N'-tetraacetic acid (BAPTA). 6-Keto prostaglandin F1 alpha production during 2 and 10 h incubation period was also inhibited by 1.2 mM ethyleneglycol-bis-(beta-aminoethylether)-N,N,N',N'-tetraace tic acid (EGTA) (41 +/- 12 and 53 +/- 17% inhibition, respectively). Further, ancrod-generated fibrin caused a rapid-onset increase in [3h]inositol monophosphate (IP1) formation in endothelial cells. This increase in IP1 was significantly inhibited by 1 mM Gly-Pro-Arg-Pro, 1 mM neomycin or 100 ng/ml pertussis toxin. At the same time, neomycin and pertussis toxin also significantly inhibited 6-keto prostaglandin F1 alpha synthesis of endothelial cells stimulated by ancrod-generated fibrin. Additionally, the increment of IP1 production as well as prostacyclin production were significantly inhibited by monoclonal antibodies directed against alpha v beta 3. These results suggest that intra- and extra-cellular Ca2+ participate in prostacyclin synthesis stimulated by ancrod-generated fibrin. Ancrod-generated fibrin stimulates pertussis toxin-sensitive G-protein regulated phosphoinositide breakdown, which is responsible for prostacyclin synthesis. This augmentation in prostacyclin synthesis and phosphoinositide breakdown caused by ancrod-generated fibrin area, at least in part, mediated by fibrin binding to integrin alpha v beta 3 on endothelial cells.
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PMID:Integrin alpha v beta 3 and phospholipase C regulate prostacyclin formation of endothelial cells caused by ancrod-generated fibrin. 885 Nov 76


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