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:3.1.4.3 (phospholipase C)
18,461 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

There are multiple mechanisms whereby ACE inhibitors could be beneficial during myocardial ischemia and reperfusion, including: i) reduced formation of angiotensin II, ii) decreased metabolism of bradykinin, iii) antioxidant activity, and iv) possibly other unknown mechanisms. Reduced formation of angiotensin II should be beneficial because this peptide exerts several actions that are potentially detrimental to the ischemic/reperfused myocardium, including vasoconstriction, increased release of norepinephrine, stimulation of phospholipase C and/or A2, and increased afterload with an attendant increase in oxygen demands. Reduced metabolism of bradykinin could be beneficial by increasing myocardial glucose uptake, by causing vasodilation, and by stimulating production of endothelium-derived relaxing factor and prostacyclin. Although earlier studies suggested that sulfhydryl-containing ACE inhibitors scavenge superoxide anions, recent data have shown that these drugs scavenge hydroxyl radical and hypochlorous acid with no effect on superoxide anion. Studies in isolated hearts have demonstrated that ACE inhibitors attenuate the metabolic, arrhythmic, and contractile dearrangements associated with ischemia and reperfusion, and have suggested that such beneficial effects are mediated by potentiation of bradykinin and/or increased synthesis of prostacyclin. Studies in models of myocardial stunning after brief (15-min) ischemia in vivo (anesthetized dogs) suggest that ACE inhibitors enhance the recovery of contractile function after a single brief ischemic episode. No data are available regarding the effect of these drugs on myocardial stunning after a prolonged, partly reversible episode, after multiple consecutive brief ischemic episodes, and after global ischemia. The mechanism for the salutary effects of ACE inhibitors on stunning remains a mystery. It may involve an antioxidant action (in the case of thiol-containing molecules) or potentiation of prostaglandins (in the case of non-thiol-containing molecules). What is clear is that the enhanced recovery of function effected by these drugs is not due to hemodynamic effects, inhibition of the converting enzyme per se, or an "antischemic" action (since the drugs were effective when given at the time of reperfusion). The effects of ACE inhibitors on myocardial infarct size remain controversial. Further studies will be necessary to conclusively establish whether ACE inhibitors can protect against the detrimental effects of myocardial ischemia and reperfusion. Nevertheless, the evidence provided thus far is encouraging and warrants an in-depth assessment of the role of these drugs in attenuating myocardial ischemia/reperfusion injury.
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PMID:Effect of angiotensin-converting enzyme inhibitors on myocardial ischemia/reperfusion injury: an overview. 835 31

Endothelial cell activation by thrombin is a key event in wound healing, inflammation, and hemostasis. To better define thrombin-endothelial cell interactions we synthesized several peptides of varying length corresponding to the initial 14 amino acid sequence of the cloned human platelet thrombin receptor after cleavage at an arginine41 site (R/SFLLRNPNDKYEPF). Thrombin receptor activating peptides (TRAPs) as short as 5 amino acids induced significant levels of PGI2 synthesis and expression of PDGF mRNA in human endothelium and produced dose-dependent cellular contraction and permeability of confluent human umbilical vein and bovine pulmonary artery endothelial monolayers. To explore whether TRAPs utilized similar signal transducing pathways as alpha-thrombin to accomplish endothelial cell activation, phospholipase C production of the Ca2+ secretagogue IP3 was measured and detected 10 seconds after either TRAP 7 or alpha-thrombin. Furthermore, TRAPs ranging from 5-14 residues induced significant dose-dependent increases in Fura-2 fluorescence indicative of Ca2+(1) mobilization. These results indicate that thrombin-mediated proteolytic cleavage of the human and bovine thrombin receptor initiates stimulus/coupling responses such phospholipase C activation, Ca2+ mobilization, and protein kinase C activation. The functional consequence of this cellular activation via the cleaved receptor is enhanced cellular contraction, barrier dysfunction, PGI2 synthesis, and expression of PDGF mRNA.
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PMID:Thrombin receptor activating peptides induce Ca2+ mobilization, barrier dysfunction, prostaglandin synthesis, and platelet-derived growth factor mRNA expression in cultured endothelium. 836 Feb 59

ATA is a novel anticoagulant polymeric anionic aromatic compound that inhibits von Willebrand factor binding to platelet glycoprotein Ib and thereby prevents ristocetin- and shear stress-induced platelet aggregation. To investigate its mechanism of action, ATA fractions of homogeneous M(r) have been prepared by size exclusion chromatography. ATA fractions of M(r) > or = 2,500 are most effective at inhibiting vWF-mediated platelet aggregation, and ATA of M(r) = 2,500 also inhibits thrombin-induced platelet activation. Paradoxical results were observed in studies of ATA with M(r) = 6,400. This fraction of ATA stimulates aggregation of washed platelets or platelet-rich-plasma. The dose/response of aggregation shows a bell-shaped curve with maximal aggregation at approximately 2 micrograms/ml. Platelet aggregation is associated with phosphoinositide turnover and protein kinase C- and calcium-dependent protein phosphorylation. Platelet signalling responses to ATA are inhibited by platelet pretreatment with PGI2 or dibutyryl-cyclic AMP, but are unaffected by inhibiting platelet cyclooxygenase with aspirin. These results suggest that M(r) 6,400 ATA directly activates platelet phospholipase C to initiate platelet aggregation. This effect, unique to M(r) 6,400 ATA, could potentially mitigate ATA's beneficial anti-thrombotic effect on vWF-mediated platelet responses, and should be considered when analyzing results of experiments that utilize unfractionated ATA.
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PMID:M(r) 6,400 aurin tricarboxylic acid directly activates platelets. 836 37

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

ATP is a well-known inducer of prostacyclin and nitric oxide release from vascular endothelial cells. These responses are mediated by P2 receptors coupled to a phospholipase C. We have investigated the influence of ATP on the control of adenosine 3',5'-cyclic monophosphate (cAMP) in bovine aortic endothelial cells. ATP produced a slight increase in the cAMP content of unstimulated endothelial cells. A more impressive response to ATP (5-fold) was observed in forskolin-stimulated cells. The rank orders of potency of various ATP analogues were strikingly different for the increase in cAMP and the accumulation of inositol phosphates. The action of ATP was unaffected by indomethacin. Protein kinase C downregulation produced only a partial inhibition of the ATP response. The effect of phorbol 12-myristate 13-acetate and bradykinin on the forskolin-induced accumulation of cAMP was much smaller than that of ATP. Neither adenosine deaminase nor AMP deaminase decreased the response to ATP, which thus cannot result from the ATP degradation into adenosine. However, 8-(p-sulfophenyl)theophylline inhibited the responses to both ATP and adenosine. In conclusion, ATP enhances the accumulation of cAMP in endothelial cells. This action appears to be the sum of two components: a minor one resulting from kinase C activation and a major one mediated either by a direct interaction of ATP with A2 receptors, or by putative methylxanthine-sensitive P2 receptors.
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PMID:Enhancement of endothelial cAMP accumulation by adenine nucleotides: role of methylxanthine-sensitive sites. 838 57

Human platelet activation is associated with, and regulated by, the phosphorylation of a number of proteins. Recently, attention has been focused on tyrosine phosphorylation of proteins and their function in platelet activation. Here vanadate, an inhibitor of tyrosine phosphohydrolase, was used to examine the role that tyrosine phosphorylation plays in platelet activation. Vanadate (7.5 to 100 mumol/L) stimulated the dose-dependent aggregation of saponin-permeabilized, but not intact, platelets. Electron-microscopic studies indicated small degranulated aggregates. Vanadate-induced aggregation was inhibited by pretreatment with prostacyclin (1 to 10 nmol/L), genistein (1 to 10 micrograms/mL), aspirin (100 mumol/L), or BW755C (80 mumol/L). Aggregation was associated with the aspirin-sensitive formation of [32P]phosphatidic acid and the phosphorylation of platelet proteins, notably pleckstrin and myosin light chain. Immunoblotting studies indicated that vanadate caused the tyrosine phosphorylation of proteins of approximate molecular weights 26, 29, 32, 40, 42, 80, and 90 Kd. Preincubation with BW755C abolished the phosphorylation of the 26-, 29-, 32-, 40-, and 42-Kd proteins but not the 80- and 90-Kd proteins. Vanadate stimulated the release of [3H]-arachidonic acid that was not affected by pretreatment with BW755C. The subsequent conversion of [3H]-arachidonic acid to [3H]-thromboxane A2 was significantly inhibited. These findings show that vanadate stimulates platelets by promoting arachidonic acid release from phospholipids. Tyrosine phosphorylation, potentially of the 80- or 90-Kd proteins, may regulate a platelet phospholipase A2. The release arachidonic acid was converted to thromboxane A2 that produced secondary effects such as phospholipase C activation, protein phosphorylation, and aggregation, and was associated with the tyrosine phosphorylation of the 26-, 29-, 32-, 40-, and 42-Kd proteins.
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PMID:Vanadate activates platelets by enhancing arachidonic acid release. 848 13

The adequate biological function of the renin-angiotensin system in blood pressure regulation and volume control involves additional factors for a fully balanced response. This includes arachidonic acid-derived lipid mediators, the eicosanoids. Angiotensin II (Ang II) causes (AT1)-receptor mediated stimulation of phospholipase C, resulting in generation of IP3 (inositol triphosphate) and activation of protein kinase C, elevated cytosolic Ca+ and stimulation phospholipase A2. These processes culminate in the generation of cell-specific eicosanoids and their autocrine action on the generating cell or paracrine effects on cells in the vicinity. In vascular tissue, liberated arachidonic acid is mainly converted into vasodilator prostaglandins, i.e. prostacyclin (PGI2) and PGE2. These prostaglandins may attenuate any direct Ang II-induced vasoconstriction, lower systemic vascular resistance and stimulate renal sodium excretion. In some vessels, arachidonic acid released by Ang II may also be converted to vasoconstrictor eicosanoids, i.e. thromboxane A2, PGF2 alpha and 12-HETE. The biological significance of endogenous eicosanoid generation becomes evident if vasoactive eicosanoids become limiting factors for maintaining homoiostasis, i.e. in the fetal circulation, Bartter's syndrome and congestive heart failure where vasodilating eicosanoids (PGE2, PGI2) are involved in maintenance of low vascular resistance and reduced or absent vasoconstriction by Ang II. Vasoconstrictor eicosanoids (thromboxane A2, PGF2 alpha, 12-HETE) contribute to high blood pressure in (renovascular) hypertension and pregnancy-induced hypertension. Alternatively, generation of vasodilator prostaglandins may be reduced in these situations. The vascular renin-angiotensin system is subject to the action of a number of drugs and chemicals, most notably specific inhibitors of the angiotensin-converging enzyme and drugs affecting kidney function (furosemide) and/or vessel tone (propranolol).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Prostaglandin-mediated actions of the renin-angiotensin system. 849 70

The mechanism of the antiplatelet functions of SM-10906, the active form of the 3-oxa-methano-prostaglandin (PG) I1 analog SM-10902, was examined in rat platelets. SM-10906 activated adenylate cyclase in crude membrane fractions, and inhibited platelet aggregation and release of adenine nucleotides stimulated by thrombin. SM-10906 also inhibited malondialdehyde production induced by thrombin, but not that induced by arachidonic acid. This may account for its inhibitory effects on phospholipase A2. SM-10906 prevented thrombin-induced inositol 1,4,5-trisphosphate production, Ca++ mobilization from intracellular Ca storage and 45Ca++ influx into platelets, which were all reversed by pretreatment with the adenylate cyclase inhibitor 2',5'-dideoxyadenosine. PGI2 and PGE1 have the same antiplatelet profiles in the order of PGI2 > or = SM-10906 > PGE1. These results indicate that SM-10906 as well as PGI2 and PGE1 may exert antiplatelet activities by stimulating adenylate cyclase to prevent thrombin-induced phospholipase C and A2 activations and increase in cytosolic Ca++ level.
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PMID:Antiplatelet functions of a stable prostacyclin analog, SM-10906 are exerted by its inhibitory effect on inositol 1,4,5-trisphosphate production and cytosolic Ca++ increase in rat platelets stimulated by thrombin. 853 26

1. The release of prostacyclin (PGI2) from vascular endothelial cells is stimulated by ATP acting at G protein-coupled P2-purinoceptors. Here we investigate the hypothesis that tyrosine protein phosphorylations are involved in this response. 2. The use of Western blots with anti-phosphotyrosine antibodies showed that 30 microM 2MeSATP (selective for P2Y-purinoceptors), 300 microM UTP (selective for P2U-purinoceptors) and 300 microM ATP (effective at both these purinoceptors), each stimulate the tyrosine phosphorylation of proteins in bovine cultured aortic endothelial cells. Each of these agonists also stimulates 6-keto PGF1 alpha accumulation in the medium (an index of PGI2 release) in these cells in the same period. 3. The tyrosine kinase inhibitor, genistein, inhibits the 6-keto PGF1 alpha response with the same concentration-dependency (1-100 microM) as the tyrosine phosphorylation response. 4. Tyrphostin, a structurally and functionally distinct tyrosine kinase inhibitor, is also a potent inhibitor (0.1-10 microM) of the 6-keto PGF1 alpha response. 5. Neither tyrphostin nor genistein inhibit the phospholipase C response to P2-purinoceptor stimulation. Furthermore, these inhibitors do not affect the 6-keto PGF1 alpha response to ionomycin. 6. These results show that the regulation of vascular endothelial cells by ATP acting at both P2Y- and P2U-purinoceptors involves the stimulation of tyrosine phosphorylation, and suggest that this is a necessary event for the purinoceptor-mediated stimulation of PGI2 production.
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PMID:Evidence for requirement of tyrosine phosphorylation in endothelial P2Y- and P2U- purinoceptor stimulation of prostacyclin release. 859 Sep 71

1. Enhanced synthesis of prostacyclin (PGI2) and inositol polyphosphates in bovine aortic endothelial cells in response to ATP and ADP is mediated by co-existing P2Y- and P2U-purinoceptors. Here we examine the regulation of these responses by isoforms of protein kinase C (PKC). 2. Immunoblots with antisera specific for 8 different PKC isoforms revealed the presence of alpha, epsilon and zeta, while no immunoreactivity was found for beta, gamma, delta, eta and theta isoforms. PKC-alpha was largely cytosolic in unstimulated cells and almost all translocated to the membrane (Triton X-100 soluble) after a 1 min treatment with the PKC activating phorbol myristate acetate (PMA); PKC-epsilon was always in a Triton X-100 insoluble membrane fraction, while PKC-zeta was found in both soluble and membrane bound (Triton X-100 soluble) forms in the unstimulated cells and was unaffected by PMA. 3. Treatment with PMA for 6 h led to a 90% downregulation of PKC-alpha, while the immunoreactivity to the epsilon and zeta isoforms remained largely unchanged. 4. After either 10 min or 6 h exposure to PMA the PGI2 response to activation of both receptors was enhanced, while the inositol 1,4,5-trisphosphate response to P2Y-purinoceptor activation was substantially attenuated and the P2U-purinoceptor response was unchanged. Thus the PGI2 response to PMA under conditions when 90% of the PKC-alpha was lost resembles that seen on acute stimulation of PKC by PMA, and the PGI2 response does not correlate with phospholipase C response. 5. Inhibition of PKC with the isoform non-selective inhibitors, Ro 31-8220 and Go 6850 abolished the PGI2 response to both P2U- and P2Y-purinoceptor stimulation. However, Go 6976, which preferentially inhibits Ca2+ sensitive isoforms (such as PKC-alpha) and not Ca2+ insensitive isoforms (such as PKC-epsilon), had no effect on the PGI2 response. 6. The results show that there is a requirement for PKC in the stimulation of PGI2 production by endothelial P2Y- and P2U-purinoceptors. Both downregulation and inhibition studies show that PKC-alpha is not responsible for the regulation of the response to P2-purinergic stimulation, and imply that the response is mediated by PKC-epsilon (PKC-zeta is unresponsive to PMA), or an as yet uncharacterized PKC isoform.
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PMID:Protein kinase C isoforms in bovine aortic endothelial cells: role in regulation of P2Y- and P2U-purinoceptor-stimulated prostacyclin release. 873 84


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