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)

Eicosanoids (prostaglandins, leukotrienes, thromboxane A2 and other metabolites of C-20 polyunsaturated fatty acids) have numerous effects in the cardiovascular system. Direct inotropic actions have been repeatedly described, but appear in only very few cases to be due to direct modification of the inotropic state of the heart. Specific eicosanoid receptors have been identified on the surface of the sarcolemmal membrane. Signal transduction pathways in the cardiac myocyte involve the adenylate cyclase/cAMP system or stimulation of the phospholipase C/IP3 pathway. In general, concentrations of eicosanoids which affect myocardial contractility are higher as the response is less predictable than the effects on platelet function or vessel tone. Therefore, eicosanoid-induced extracardiac effects may be superimposed to more direct changes in the contractile state of the intact heart in vitro or in vivo. In contrast to non-failing hearts, there is a significant improvement of the contractile function in contractile failure ("stunning", ischemia, congestive heart failure) by vasodilating prostaglandins (e.g., PGI2). The mechanism of this action is still unknown.
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PMID:Inotropic actions of eicosanoids. 131 58

Intracellular signaling systems that are involved in growth of cardiac myocytes and that are modified in congestive heart failure include the alpha 1- and beta-adrenergic systems and angiotensin II. These systems include G-protein-linked hormone receptors and their membrane enzyme including adenylyl cyclase and phospholipase C. In addition, membrane enzymes, and adenylyl cyclase in particular, respond directly to stretch of the cell membrane with an increase in cAMP formation. Furthermore, interactions between stretch and hormonal stimuli can potentiate each other and result in enhanced signal generation.
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PMID:Cellular aspects of cardiac failure. 838 4

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

Although phosphoinositide-specific phospholipase C (PLC) is involved in signal transduction mechanisms of the myocardial cell. very little is known about its status in congestive heart failure (CHF). We have examined the PLC activity in sarcolemmal and cytosolic fractions isolated from the viable left ventricle of rats at 8 weeks (moderate stage of CHF) and 16 weeks (severe stage of CHF) after occlusion of the left anterior descending coronary artery; the hypertrophied right ventricle was used for comparison. At 8 weeks, the hydrolysis of phosphatidylinositol 4,5-bisphosphate by sarcolemmal PLC was reduced by 37% of sham control values only in the left ventricle, whereas at 16 weeks, PLC-mediated hydrolysis was depressed in both left and right ventricles by 25% and 30%, respectively. The hydrolysis of phosphatidylinositol 4-monophosphate (PIP) was reduced by 25% of control value only in the severely failing left ventricle, while the phosphatidylinositol (PI) hydrolysis remained unaltered. Kinetic studies of PLC activity in the left ventricle showed a depression of V(max) at moderate and severe failure stages, whereas the affinity for the substrate was increased in the left ventricle at 8 weeks and decreased in the right ventricle at 16 weeks. The only difference observed between experimental and control groups at the cytosolic level, was a significant enhancement of PLC activity in the severely failing left ventricle when PIP was given as a substrate, and in the corresponding right ventricle when PI was the substrate. The results of this study identify time-related defects in sarcolemmal PLC in right and left ventricles during the development of CHF due to myocardial infarction.
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PMID:Identification of changes in cardiac phospholipase C activity in congestive heart failure. 904 38

In this review, the role of tyrosine kinases in angiotensin II-mediated signal transduction pathways in vascular smooth muscle is discussed. Angiotensin II was isolated by virtue of its vasoconstrictor abilities and has long been thought to play a critical role in hypertension. However, recent studies indicate important roles for angiotensin II in inflammation, atherosclerosis, and congestive heart failure. The expanding role of angiotensin II indicates that multiple signal transduction pathways are likely to be activated in a tissue-specific manner. Exciting recent data show that angiotensin II directly stimulates tyrosine kinases, including pp60(c-src) kinase (c-Src), focal adhesion kinase (FAK), and Janus kinases (JAK2 and TYK2). Angiotensin II may activate receptor tyrosine kinases, such as Axl and platelet-derived growth factor, by as-yet-undefined autocrine mechanisms. Finally, unknown tyrosine kinases may mediate tyrosine phosphorylation of Shc, Raf, and phospholipase C-gamma after angiotensin II stimulation. These angiotensin II-regulated tyrosine kinases appear to be required for angiotensin II effects, such as vasoconstriction, proto-oncogene expression, and protein synthesis, on the basis of studies with tyrosine kinase inhibitors. Thus, understanding angiotensin II-stimulated signaling events, especially those related to tyrosine kinase activity, may form the basis for the development of new therapies for cardiovascular diseases.
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PMID:Angiotensin II signal transduction in vascular smooth muscle: role of tyrosine kinases. 913 Apr 41

Originally known to be a vasoconstrictor and thought to play a critical role in hypertension, angiotensin II has recently emerged to be important in inflammation, atherosclerosis and congestive heart failure. The expanding role of angiotensin II implies that multiple signal transduction pathways are likely to be activated in a tissue-specific manner. Recent data show that angiotensin II stimulates not only cytoplasmic tyrosine kinases including c-Src, focal adhesion kinase (FAK), and Janus kinases (JAK2 and TYK2), but also may transactivate receptor tyrosine kinases such as Axl and PDGF by as yet undefined autocrine/paracrine mechanisms. Finally, tyrosine kinases, which mediate tyrosine phosphorylation of key signal mediators such as Shc, Raf, and phospholipase C-gamma following angiotensin II stimulation, remain to be defined. These tyrosine kinases, activated by angiotensin II, appear to be required for angiotensin II effects such as vasoconstriction, proto-oncogene expression, protein synthesis, and cell proliferation. Thus, it is important to understand angiotensin II-mediated signaling events, especially those related to tyrosine kinase activity, to develop new therapies for cardiovascular diseases.
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PMID:Angiotensin II signal transduction in vascular smooth muscle cells: role of tyrosine kinases. 921 88

The arterial wall is structurally and functionally compartmentalized. Each compartment is characterized by a specific cell type and by specific interactions. The endothelial compartment interacts with circulating blood, and the adventitial compartment with the surrounding tissue. The media, which contains the effector smooth muscle cells, perceives centrifugal messages from the endothelium and centripetal messages from metabolically active tissues, from adventitial nerve endings, and from peptides produced in the interstitium. The degree of contraction or relaxation of the vascular smooth muscle cells characterizes the general vasomotor tone, which governs the local blood pressure level and distributes the flow according to metabolic needs. The main physiologic vasoactive agent is nitric oxide (NO) and is produced by the endothelium. In disease states, other agents can become predominant in centrifugal parietal messages. NO is produced by type 3 NO synthase, an enzyme that is constitutively expressed by endothelial cells. The activity of this enzyme on its substrate, arginine, is regulated by the concentration of free calcium and by intracellular phosphorylations. Several peptides, including receptors, are coupled to the phospholipase C pathway in the endothelial cell; endothelial growth factors such as FGF and VEGF, enhance the activity of endothelial NO synthase. However, the main physiologic factor responsible for endothelial NO synthase activation is the shearing stress produced by friction of the flowing blood against the immobile vessel wall. This shearing stress constantly adjusts the diameter of conductance vessels to peripheral metabolic needs. Expression of endothelial NO synthase is modulated by the chronic effects of the same agents. NO has a vasodilating effect that is mediated by the generation of cyclic GMP. Cyclic GMP and cyclic AMP are the main second messengers in smooth muscle cell relaxation. NO binds to a heme-protein, soluble guanylate cyclase, that converts GMP to cyclic GMP. Kinase-G is the main target for cyclic GMP in the smooth muscle cell. Kinase-G phosphorylates phospholambans and releases the repumping activity of calcium ATPase. More importantly, kinase-G phosphorylates the protein G that links seven-domain membrane-spanning receptors to phospholipases, thus inhibiting coupling between the ligand-receptors interaction and the intracellular signaling process that leads to contraction. NO can relax the smooth muscle cell only in the presence of a preexisting contractile tone. Conversely, absence of NO enhances the preexisting contractile tone. All these notions can be analyzed via the experimental model of L-NAME-induced chronic NO synthase blockade in rats. The decrease in parietal cyclic GMP seen in this model is associated with an increase in contractile tone that translates into systemic arterial hypertension. The increase in contractile tone can be blocked by renin-angiotensin system inhibitors. Chronic blockade of NO production rapidly induces vascular wall phenotype changes that lead to renal failure, ischemic stroke, and fibrosis of target organs. These phenotype changes may be related to the increase in the oxidative potential of the various types of parietal cells, as suggested by the abnormal presence of inflammatory cells and by the increased expression of inflammation mediators including cyclooxygenase II, inducible NO synthase, and adhesion molecules such as ICAM and VCAM. This model therefore holds promise for elucidating interactions between NO and arteriosclerosis. NO system dysfunction is also seen in other cardiovascular disorders, including congestive heart failure.
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PMID:[Role of endothelial nitric oxide in the regulation of the vasomotor system]. 976 14

In this review, the signal events regulated by angiotensin II (AngII) in vascular smooth muscle are analyzed based on activation of specific tyrosine kinases. AngII has been shown to play a critical role in the pathogenesis of hypertension, inflammation, atherosclerosis, and congestive heart failure. The expanding role of AngII indicates that multiple signal transduction pathways are likely to be activated in a tissue-specific manner. Although at least three AngII receptors have been characterized, it seems that the AngII type I receptor (AT1R) is physiologically most important since pharmacologic inhibitors of the AT1R block most AngII signal events and have beneficial effects on cardiovascular disease. The AT1R is a seven transmembrane-spanning G protein-coupled receptor that regulates intracellular signal events by activation of Gq and Gi. However, many recent data indicate that activation of tyrosine kinases by several different mechanisms contributes to AngII effects in target tissues. Tyrosine kinases activated by AngII include c-Src, focal adhesion kinase (FAK), Pyk2 (CADTK), Janus kinases (JAK2 and TYK2), and the receptor tyrosine kinases Ax1, epidermal growth factor, and platelet-derived growth factor. Finally, unknown tyrosine kinases may mediate tyrosine phosphorylation of paxillin, Shc, Raf, and phospholipase C-gamma after AngII stimulation. These AngII-regulated tyrosine kinases seem to be required for AngII effects such as vasoconstriction, proto-oncogene expression, and protein synthesis based on studies with tyrosine kinase inhibitors. Thus, understanding AngII-stimulated signaling events, especially those related to tyrosine kinase activity, may form the basis for the development of new therapies for cardiovascular diseases.
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PMID:Angiotensin II signal transduction in vascular smooth muscle: pathways activated by specific tyrosine kinases. 989 42

We have examined the changes in quantity and activity of cardiac sarcolemmal (SL) phosphoinositide-phospholipase C (PLC)-beta(1), -gamma(1), and -delta(1) in a model of congestive heart failure (CHF) secondary to large transmural myocardial infarction (MI). We also instituted a late in vivo monotherapy with imidapril, an ANG-converting enzyme (ACE) inhibitor, to test the hypothesis that its therapeutic action is associated with the functional correction of PLC isoenzymes. SL membranes were purified from the surviving left ventricle of rats in a moderate stage of CHF at 8 wk after occlusion of the left anterior descending coronary artery. SL PLC isoenzymes were examined in terms of protein mass and hydrolytic activity. CHF resulted in a striking reduction (to 6-17% of controls) of the mass and activity of gamma(1)- and delta(1)-isoforms in combination with a significant increase of both PLC beta(1) parameters. In vivo treatment with imidapril (1 mg/kg body wt, daily, initiated 4 wk after coronary occlusion) improved the contractile function and induced a partial correction of PLCs. The mass of SL phosphatidylinositol 4,5-bisphosphate and the activities of the enzymes responsible for its synthesis were significantly reduced in post-MI CHF and partially corrected by imidapril. The results indicate that profound changes in the profile of heart SL PLC-beta(1), -gamma(1), and -delta(1) occur in CHF, which could alter the complex second messenger responses of these isoforms, whereas their partial correction by imidapril may be related to the mechanism of action of this ACE inhibitor.
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PMID:Changes in sarcolemmal PLC isoenzymes in postinfarct congestive heart failure: partial correction by imidapril. 1040 80

Activation of protein kinase C (PKC) has been implicated as playing a key role in the pathogenesis of cardiac hypertrophy. This study investigates the response of several signal transduction proteins responsible for PKC activation during the transition from compensated pressure-overload hypertrophy (POH) to congestive heart failure (CHF). Pressure overload was produced on male, adult, Hartley strain guinea pigs using a ligature around the descending thoracic aorta. Sham-operated controls, POH, and CHF groups were identified based on left ventricular hypertrophy, pulmonary congestion, and isolated heart Langendorff mechanics. Quantitative immunoblotting revealed phospholipase C (PLC)-betaI and Galphaq were unchanged during POH and CHF, as were RGS2, RGS3, and RGS4 (regulators of G protein signaling, which are activators of intrinsic GTPase activity). Translocation of PKC-alpha, -epsilon, and -gamma from cytosolic to membranous fractions were significantly increased during POH and CHF. Cytosolic PKC activity was also elevated during POH. We conclude that differential PKC activation may be mediated by increases in Galphaq and PLC-betaI activity rather than upregulation of expression.
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PMID:PKC translocation without changes in Galphaq and PLC-beta protein abundance in cardiac hypertrophy and failure. 1060 Aug 49


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