Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P00750 (PLA)
 16,800 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Platelets play a vital role in mediating the activity of plasma fibrinolytic system. They have both the potential to inhibit as well as to activate fibrinolysis. Just as platelet can affect thrombolysis, thrombolytic agents can have reciprocal effects on platelet function. Accumulating evidence indicates that thrombolysis induced both by streptokinase and t-PA results in rapid activation of platelets, the phenomenon being possibly responsible for reocclusion of arteries after successful thrombolysis. However, caution is required in comparing the results of the various studies because of differences in the thrombotic models employed, with the major variables being the mechanism of thrombus formation (in vivo or in vitro), the platelet concentrations and the doses of investigated agent. Various studies indicate that adjunctive therapy with anti-platelet agents, such as inhibitors of cyclooxygenase, inhibitors of thromboxane A2-synthase and activators of platelet cyclic-AMP or -GMP may lower the dose of the thrombolytic agent required to attain reperfusion.
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PMID:Platelets in fibrinolytic system. 877 Jul 85

In order to reach the sites of inflammation, lymphocytes leave the bloodstream and migrate into peripheral tissues, in a process involving integrin-mediated adhesion to the vascular endothelium, followed by transmigration across the endothelial barrier and through the underlying interstitial matrix. We have investigated the role of the plasminogen activator/plasmin system in normal T cell migration. Receptors for urokinase plasminogen activator (uPAR) were not expressed in resting T lymphocytes, but could be efficiently induced at the mRNA and protein level by coclustering of the antigen receptor complex and beta1 or beta2 integrins, through a signalling pathway involving both protein kinase C activation and an increase in intracellular cyclic AMP. Catalytic activation of plasminogen by uPAR-expressing T cells promoted their migration through an extracellular matrix in vitro. Plasmin-induced invasion was inhibited by plasmin-and urokinase inhibitors and by anti-uPAR antibodies. Finally, cytofluorimetric and immunohistochemical analysis of primary human tumor specimens showed the presence of uPAR positive infiltrating T cells in vivo. Collectively, these findings suggest that plasminogen activation may play a role in lymphocyte migration in vivo, and that integrin-dependent expression of membrane-associated endopeptidases could represent an additional step in the regulated process of leukocyte transmigration.
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PMID:Integrin-dependent induction of functional urokinase receptors in primary T lymphocytes. 878 76

Defibrotide, a polydeoxyribonucleotide, has been found to modulate endothelial cell function, causing an increase in tissue plasminogen activator (t-PA) levels, a decrease in plasminogen activator inhibitor (PAI) levels, and an increase in prostaglandin I2 (PGI2) formation in humans. Defibrotide has no direct anticoagulant effect but has a synergistic action with heparin. A strong antithrombotic effect has been observed in animal models. Thus, defibrotide has a beneficial effect in cases of deep venous thrombosis (DVT), peripheral obliterative vascular disorder (POVD), stroke, vasculitis, and thromboembolism. Defibrotide also inhibits platelet function and activation. A significant decrease in platelet aggregate formation on the suture line in microarterial anastomosis in rats is one way defibrotide can inhibit platelet function and activation. In humans, a slight prolongation' of the lag period in collagen-induced aggregation has been observed. In addition, a slight decrease in the maximum amplitude of the secondary wave of ADP and adrenalin-induced aggregations was also found. Platelet adhesion is diminished, the platelet differential count on formvar membrane is altered, and platelet aggregate formation is significantly inhibited. With an increase in platelet cyclic AMP (cAMP) content and a decrease in malonyl dialdehyde (MDA) and thromboxane B2 (TXB2) formation, the levels of platelet secretion products such as PF-4 and beta-thromboglobulin (beta-TG) in plasma decreased progressively. It was also demonstrated that the 14C-glucose transport defect of the platelet membrane of atherosclerotic patients was partially corrected with defibrotide treatment.
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PMID:Effect of defibrotide on platelet function. 880 24

The plasminogen activators tPA and uPA, and their inhibitors, PAI-1 and PAI-2, have been associated with epithelial homeostasis and wound healing. In these studies, we investigate the effect of the steroid hormone hydrocortisone, a commonly used therapeutic modality for skin, on PAs/PAIs in serum- and plasminogen-free primary cultures of murine keratinocytes. SDS-PAGE fibrin zymography showed that addition of 1 microM hydrocortisone to cultures significantly reduced tPA fibrinolytic activity in both cell extracts and conditioned medium. uPA activity in conditioned medium was similarly inhibited. Cells were also cultured in the presence of dibutyryl cyclic AMP (dbcAMP). dbcAMP (5 mM) alone enhanced uPA and tPA fibrinolytic activity in conditioned medium, but this increase was diminished in the presence of 1 microM hydrocortisone. Immunoblots revealed a three- to fivefold induction of free PAI-1 by hydrocortisone which was partially blocked by dbcAMP. Northern blots showed that PAI-1 mRNA increased threefold 2 h after addition of hydrocortisone and remained elevated at least 8 h. In contrast, uPA and tPA mRNA were unchanged over the same time course. uPA, tPA, and PAI-1 mRNA increased in the presence of dbcAMP; levels remained elevated at least 8 h. HC suppressed the induction of uPA and tPA by dbcAMP. Studies directed at identifying plasminogen mRNA showed that in this culture system, keratinocytes produce no plasminogen mRNA either in the presence or in the absence of hydrocortisone or dbcAMP. Collectively, these results show that keratinocyte plasminogen activator activity is suppressed by hydrocortisone as a function of increased PAI-1 combined with an attenuation of PA induction by agents that increase intracellular cAMP. These results provide additional information to further define the mechanism by which glucocorticoids inhibit wound healing.
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PMID:Hydrocortisone regulates the dynamics of plasminogen activator and plasminogen activator inhibitor expression in cultured murine keratinocytes. 966 8

The mechanism by which moderate alcohol ingestion lowers the risk of cardiovascular disease is unknown but may be due, in part, to the ability of alcohol to increase the level of tissue-type plasminogen activator (t-PA). Human endothelial cells were treated with low concentrations of ethanol (0.25-25 mM, 0-24 h), which are associated with moderate alcohol consumption. Although treatment with ethanol alone did not affect t-PA gene transcription or mRNA expression, it augmented isoproterenol (ISO)-stimulated t-PA gene transcription and mRNA levels by 3.4- and 2.8-fold, respectively, and decreased plasminogen activator inhibitor-1 mRNA levels by 65%. These effects of ethanol correlated with 2.5- and 6.9-fold increases in ISO-stimulated cyclic AMP levels and 4x-cyclic AMP response element heterologous promoter activity, respectively. To determine whether alcohol-induced changes in agonist-stimulated cyclic AMP levels were because of modulation of guanine nucleotide-binding proteins (G proteins), we assessed the effects of ethanol on Galphas and Galphai2. Although ethanol did not affect the expression of Galphas or Galphai2, it increased ISO-stimulated Galphas GTPase and GTP binding activity by 2.2- and 2.9-fold and decreased UK14304-stimulated Galphai2 GTPase and GTP binding activity by 38 and 80%. These results indicate that treatment with relatively low concentrations of ethanol enhances agonist-stimulated cyclic AMP-dependent t-PA gene transcription in vascular endothelial cells through differential modulation of G protein.
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PMID:Activation of guanine nucleotide-binding proteins and induction of endothelial tissue-type plasminogen activator gene transcription by alcohol. 1020 29

Although phospholipase A(2) (PLA(2)) is of importance for insulin secretion, it is not established how it relates to other signalling mechanisms. This study examined the crosstalk between PLA(2) and the cyclic AMP (cAMP)-protein kinase A (PKA) pathway in isolated rat islets. Forskolin, IBMX, and dbcAMP reduced [(3)H]arachidonic acid ([(3)H]AA) efflux from prelabelled islets during PLA(2) activation by mellitin or cholecystokinin (CCK-8), while efflux induced by carbachol was unaffected. The PKA inhibitor myrPKI(14-22) prevented this reduction of CCK-8-induced efflux. Glucagon-like peptide-1 (GLP-1), gastric inhibitory polypeptide (GIP), and vasoactive intestinal polypeptide (VIP) diminished CCK-8-induced efflux. Also in the absence of Ca(2+), forskolin/IBMX and dbcAMP reduced CCK-8-induced efflux. In parallel with effects on [(3)H]AA, the expected additive insulin secretion induced by mellitin or CCK-8 in combination with forskolin or GLP-1, respectively, was reduced. In conclusion, the cAMP-PKA pathway restrains both Ca(2+)-dependent and Ca(2+)-independent PLA(2) activation, indicating a regulating crosstalk between these two pathways.
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PMID:The cyclic AMP-protein kinase A pathway restrains islet phospholipase A(2) activation. 1069 7

We have previously demonstrated that Ca(2+)/calmodulin-dependent protein kinase (CaMK) mediates pyrimidinoceptor potentiation of LPS-elicited inducible nitric oxide synthase (iNOS) induction in murine J774 macrophages. In the present paper, we have explored the role of cyclo-oxygenase (COX)-dependent prostaglandin E(2) (PGE(2)) formation in this event. In J774 macrophages predominantly expressing P2Y(6) receptors, the simultaneous addition of UTP and lipopolysaccharide (LPS) resulted in potentiated increase in PGE(2) release. UTP-induced increased PGE(2) release was demonstrated by a concomitant increase in COX-2 protein expression, and was decreased by inhibitors specific for phosphatidylinositide-phospholipase C (PI-PLC), CaMK, protein kinase C (PKC), nuclear factor-kappa B (NF-kappaB) or COX-2. NS-398 (a selective COX-2 inhibitor) reduced LPS plus UTP-elicited iNOS induction and nitrite accumulation, supporting for the positive regulation of iNOS gene expression by endogenous PGE(2). Moreover, the cyclic AMP/PKA-dependent up-regulation of iNOS expression mediated by PGE(2) was drawn from the inhibitory effects of 2',5'-dideoxyadenosine, KT5720 and H-89. Exogenous PGE(2) induced NF-kappaB activation and potentiated nitrite accumulation in response to LPS. In addition to COX-2 induction, arachidonic acid (AA) release and steady-state mRNA levels of type V secretory phospholipase A(2) (sPLA(2)) and Ca(2+)-independent PLA(2) (iPLA(2)) were also increased in the presence of LPS and UTP; the LPS-induced increase in iPLA(2) activity was also potentiated by UTP. Taken together, we conclude that UTP-mediated COX-2 and iPLA(2) potentiation and PGE(2) formation contribute to the iNOS induction, and that CaMK activation is the primary step in the UTP enhancement of COX-2 induction.
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PMID:Pyrimidinoceptor potentiation of macrophage PGE(2) release involved in the induction of nitric oxide synthase. 1086 83

This study was attempted to characterize pharmacologically the P2Y receptors triggering phospholipase A(2) (PLA(2)) activation in ampulla from frog semicircular canal. A microassay was developed to screen the abilities of UTP analogs to stimulate [(3)H]arachidonic acid release by labeled ampullas. At 26 degrees C UTP induced a dose-dependent and saturable increase of PLA(2) activity (apparent activation constant 1.3 +/- 0.4 microM, Hill coefficient 0.9 +/- 0.2, maximal stimulating factor 2.0 +/- 0.1). The rank order of potency of agonists for PLA(2) activation was UTP > or = UDP > adenosine 5'-O-(2-thiodiphosphate) = adenosine 5'-O-(3-thiotriphosphate) > or = ATP = 2-methylthio-ATP > or = ADP = diadenosine tetraphosphate > or = alpha,beta-methylene-ATP = CTP > 2' and 3'-O-(4-benzoylbenzoyl)-ATP > or = AMP = UMP >> uridine and adenosine. UTP- and 2-methylthio-ATP-induced PLA(2) activations were inhibited by U-73122, GF-109203X, and methyl arachidonyl fluorophosphate. Basal activity was stimulated by phorbol ester and epinephrine and reduced by vasotocin, isoproterenol, prostaglandin E(2), cAMP, and forskolin. H-89 restored the cAMP- and forskolin-inhibited PLA(2) activities. Results indicate that P2Y receptor-mediated PLA(2) stimulation requires phopholipase C and protein kinase C activations and basal activity is inhibited by agonist-stimulated cAMP-dependent mechanisms.
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PMID:Purine and pyrimidine nucleotide-sensitive phospholipase A(2) in ampulla from frog semicircular canal. 1120 83

1. The ability of 19 agonists to elevate Ca(2+) and inhibit forskolin-induced cyclic AMP elevation through alpha(2A)-adrenoceptors in HEL 92.1.7 cells was investigated. Ligands of catecholamine-like- (five), imidazoline- (nine) and non-catecholamine-non-imidazoline-type (five) were included. 2. The relative maximum responses were similar in both assays. Five ligands were full or nearly full agonists, six produced 20 - 70% of the response to a full agonist and the remaining eight gave lower responses (< 20%) so that their potencies were difficult to evaluate. 3. Marked differences in the potencies of the agonists with respect to the two measured responses were seen. The catecholamines were several times less potent in decreasing cyclic AMP than in increasing Ca(2+), whereas the other, both imidazoline and ox-/thiazoloazepine ligands, were several times more potent with respect to the former than the latter response. For instance, UK14,304 was more potent than adrenaline with respect to the cyclic AMP response but less potent than adrenaline with respect to the Ca(2+) response. 4. All the responses were sensitive to pertussis toxin-pretreatment. Also the possible role of PLA(2), beta-adrenoceptors or ligand transport or metabolism as a source of error could be excluded. The results suggest that the active receptor states produced by catecholamines and the other agonists are markedly different and therefore have different abilities to activate different signalling pathways.
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PMID:Agonist trafficking of G(i/o)-mediated alpha(2A)-adrenoceptor responses in HEL 92.1.7 cells. 1126 41

Previous studies have demonstrated that trophic hormone stimulation induced cyclic AMP (cAMP) formation and arachidonic acid (AA) release from phospholipids and that both these compounds were required for steroid biosynthesis and steroidogenic acute regulatory (StAR) gene expression in MA-10 mouse Leydig tumor cells. The present study further investigates the synergistic effects of the AA and cAMP interaction on steroidogenesis. To demonstrate cAMP-induced AA release, MA-10 cells were pre-loaded with 3H-AA and subsequently treated with dibutyryl cyclic AMP (dbcAMP). Stimulation with dbcAMP significantly induced AA release in MA-10 cells to a level 145.7% higher than that of controls. Lowering intracellular cAMP concentration by expressing a cAMP-phosphodiesterase significantly reduced human chorionic gonadotrophin (hCG)-induced AA release. The dbcAMP-induced AA release was inhibited significantly by the phospholipase A(2) (PLA(2)) inhibitor dexamethasone (Dex) and also by the protein kinase A (PKA) inhibitor H89, suggesting the involvement of PKA phosphorylation and/or PLA(2) activation in cAMP-induced AA release. The effect of the interaction between AA and cAMP on StAR gene expression and steroid production was also investigated. While 0.2 mM dbcAMP induced only very low levels of StAR protein, StAR mRNA, StAR promoter activity and steroid production, all of these parameters increased dramatically as AA concentration in the culture medium was increased from 0 to 200 microM. Importantly, AA was not able to induce a significant increase in steroidogenesis at any concentration when used in the absence of dbcAMP. However, when used in concert with submaximal concentrations of dbcAMP (0.05 mm to 0.5 mm), AA was capable of stimulating StAR gene expression and increasing steroid production significantly. The results from this study demonstrate that AA and cAMP act in a highly synergistic manner to increase the sensitivity of steroid production to trophic hormone stimulation and probably do so by increasing StAR gene expression.
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PMID:Interaction between arachidonic acid and cAMP signaling pathways enhances steroidogenesis and StAR gene expression in MA-10 Leydig tumor cells. 1191 46


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