Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.1.4.3 (phospholipase C)
 18,461 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The interaction of the IgG from Trypanosoma cruzi-infected mice (chagasic IgG) with cardiac cholinergic receptors by means of specific radioligand binding and by production of cholinergic-mediated cellular transmembrane signals was characterized. Chagasic IgG inhibited, in a noncompetitive manner, the binding of [3H]quinuclidinyl benzilate to the cardiac membrane. Moreover, chagasic IgG could modify all of the muscarinic cholinergic effects mediated by a G regulatory protein, i.e., decrement of atria contractility, inhibition of cAMP, or activation of the turnover of phosphoinositides via phospholipase C. The cGMP production was also increased by the antibody. The data demonstrated that chagasic IgG interacting with cardiac muscarinic cholinergic receptor triggers the biological effects associated with cholinergic-mediated cellular transmembrane signals. The implications of the results in the pathogenesis of Chagas' myocarditis are discussed.
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PMID:Chagasic IgG binding with cardiac muscarinic cholinergic receptors modifies cholinergic-mediated cellular transmembrane signals. 165 67

We have previously shown that myocardium from experimental autoimmune myocarditis expresses H1 receptors not present in normal mice heart. ThEA acting via H1 receptors, augments cyclic AMP production in atria from autoimmune myocarditis mice without any effect on atria from control mice. Addition of mepyramine before ThEA caused cyclic AMP levels to fall to a level similar to basal, confirming the H1 receptor participation. Histamine at low concentrations mimicked the ThEA action on H1 receptor-stimulation of cyclic AMP production by autoimmune myocardium. The fact that the inhibition of phospholipase C blocked the cyclic AMP stimulation by ThEA, supports the assumption that this action is secondary to receptor-mediated hydrolysis of phosphoinositides, generating some oxidative metabolites (IP3-DAG), which in turn may be responsible for the cyclic AMP effect. So, the inhibition of protein kinase C and calcium/calmodulin partially prevented the stimulatory action of ThEA on cyclic AMP levels in autoimmune myocardium, suggesting that both pathways are implicated in this effect. Data shows that the stimulation of H1 receptors by specific agonist in atria from autoimmune myocarditis mice, augments the cyclic AMP, requiring the hydrolysis of phosphoinositide cycle. The role of this cyclic AMP augmentation in myocardium from autoimmune myocarditis mice, will provide a basis to assess the role of this second messenger as an important factor in the regulation and/or modulation of the physiological behaviour of the heart in the course of autoimmune myocarditis.
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PMID:Increases in cyclic AMP levels couple to H1 receptors in atria from autoimmune myocarditis mice. 859 44

Cytotoxic T lymphocytes (CTLs) that infiltrate the heart are important immune effectors implicated in heart transplant rejection, myocarditis, and other cardiomyopathies. To investigate the mechanism(s) underlying CTL damage to the myocardium through activation of the Fas receptor (Fas/CD95/Apo-1) by the Fas ligand, we explored the interaction between peritoneal exudate CTLs (PELs), derived from perforin gene-knockout (P-/-) mice, and murine ventricular myocytes. Fas expression on isolated ventricular myocytes was demonstrated immunohistochemically. Action potentials, [Ca2+]i transients, and contractions of myocytes conjugated to P-/- PELs or treated with the apoptosis-inducing anti-Fas monoclonal antibody Jo2 were recorded. Action potential characteristics of nonconjugated myocytes and myocytes conjugated with P-/- PELs were, respectively, as follows: Vm, -73.2+/-1.5 and -53.6+/-6.4 mV (mean+/-SEM); action potential amplitude, 117.9+/-3.9 and 74.3+/-21.2 mV; and action potential duration at 80% repolarization, 17+/-6 and 42+/-13 milliseconds (all P<.05). P-/- PELs also induced early and delayed afterdepolarizations as well as arrhythmogenic activity. Diastolic [Ca2+]i increased during the cytocidal interaction with P-/- PELs, from a fluorescence ratio of 0.82+/-0.05 (n=7) to 1.98+/-0.09 (n=13) (P<.05). All of the effects caused by P-/- PELs were reproduced by incubating the myocytes with Jo2. Heparin (50 microg/mL), an antagonist of inositol trisphosphate (IP3)-operated sarcoplasmic reticulum Ca2+ channels, or U-73122 (2 micromol/L), a phospholipase C inhibitor, but not the inactive agonist U-73343, prevented Fas-mediated myocyte dysfunction. Additionally, intracellular application (through the patch pipette) of the active IP3 analogue, inositol 1,4,5-trisphosphate, but not the inactive analogue, inositol 1,3,4-trisphosphate, caused electrophysiological changes resembling those resulting from P-/- PELs and Jo2, suggesting that CTL-induced Fas-based myocyte dysfunction is mediated by IP3. We conclude that a Fas-based perforin-independent mechanism of CTL action can account for the immunopathology seen in the allotransplanted heart, myocarditis, and dilated cardiomyopathy.
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PMID:Fas (CD95/Apo-1)-mediated damage to ventricular myocytes induced by cytotoxic T lymphocytes from perforin-deficient mice: a major role for inositol 1,4,5-trisphosphate. 950 4

Cardiac tissue from autoimmune myocarditis mice was studied to evaluate the expression and biological activity of mRNA encoding H(1) receptor and iNOS. BALB/c inbred mice were immunized with heart protein and sacrificed at 20, 45 and 50 days post immunization. Heart contractility studies and RT-PCR assays were performed. Heart from autoimmune myocarditis mice show mRNA iNOS-related dysfunction with a decrease in heart contractility. This effect was accompanied with an increase production of cyclic GMP and was improved by treating autoimmune mice with an inhibitor of iNOS activity. In addition, autoimmune myocardium expressed an active histamine H(1) receptor mRNA coupled to phospholipase C. The activation of H(1) receptor by ThEA stimulated both phosphoinositide hydrolysis and heart contractility. Normal myocardium did not expressed neither iNOS mRNA nor H(1) receptor mRNA. In conclusions: the development of autoimmune cardiac dysfunction was associated with the expression of iNOS mRNA, cyclic GMP accumulation and the expression of an active histamine H(1) receptor mRNA with increase production of inositol phosphates. These protein emergence during the course of autoimmune myocarditis may be involved a distinct compensatory mechanism operating in this disease.
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PMID:Detection of mRNA encoding H(1) receptor and iNOS by RT-PCR in autoimmune myocarditis with special reference to changes in heart contractility. 1110 71

Activation of the Fas receptor in various cell types, including myocytes, triggers apoptotic as well as nonapoptotic effects. Recent studies suggest that Fas activation in the heart participates in the development of major pathologies such as myocarditis and ischemic/reperfusion insults, which are manifested by arrhythmias and mechanical dysfunction. To decipher the contribution of the Fas/FasL pathway to myocardial pathologies, we have investigated the functional consequences of Fas activation in normoxic and hypoxic ventricular myocytes. Our major findings were as follows. (1) Although Fas is constitutively expressed in ventricular myocytes, normoxic myocytes are resistant to Fas-mediated apoptosis. In contrast, hypoxia predisposes myocytes to apoptosis induced by Fas activation. The underlying mechanism is a shift in the balance between proapoptotic proteins (including Fas) and antiapoptotic proteins toward the former. (2) In normoxic myocytes, Fas activation causes a wide range of functional disturbances, which include reduction in resting potential and action potential amplitude, prolonged action potential duration, development of delayed and early after-depolarizations, occasionally culminating into arrhythmias, diastolic [Ca(2+)](i) level increase, decreased I(to) and increased I(Ca,L). (3) The above-mentioned effects in normoxic myocytes (but not Fas-mediated apoptosis in hypoxic myocytes) depend on the phospholipase C --> 1,4,5-IP(3) --> SR [Ca(2+)](i) release cascade. (4) Inhibition of tyrosine kinases with genistein blocks both the apoptotic and nonapoptotic consequences of Fas activation in ventricular myocytes. Based on these studies we propose that tyrosine phosphorylation in ventricular myocytes can serve as a novel potential target for attenuating Fas-mediated dysfunction in normoxic and hypoxic myocardium.
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PMID:The Fas receptor-1,4,5-IP3 cascade: a potential target for treating heart failure and arrhythmias. 1520 Nov 73

Stimulation of phosphoinositide hydrolysis in myocardium from autoimmune myocarditis mice by ThEA and histamine was assayed. Myocardium from autoimmune heart, but not the normal forms, specifically increased phosphoinositide turnover in the presence of histaminergic agonists. This increment was blocked by a specific H1 antagonist mepyramine and to the same extent by the phospholipase C inhibitor NCDC. By using a binding assay H1 histaminergic receptors were detected in autoimmune heart membrane preparations, but this was not observed in normal heart. These data suggest that autoimmune myocardium expressed a functional H1 receptor that could involve a distinctive mechanism operating in the disease.
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PMID:Phosphoinositide hydrolysis mediated by H1 receptors in autoimmune myocarditis mice. 1847 40