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.
Basic Res Cardiol
PMID:Inotropic actions of eicosanoids. 131 58

Catecholamines acting through beta 1- and beta 2-adrenoceptors cause positive inotropic and chronotropic effects in the human heart. In recent years, however, evidence has accumulated that in the human heart also other receptor systems can affect heart rate and/or contractility. Positive inotropic effects can be mediated by receptor systems acting through accumulation of intracellular cAMP (Gs-protein coupled receptors such as 5-HT4-like, histamine H2, and vasoactive intestinal peptide) or by receptor systems acting independent of cAMP possibly through the phospholipase C/diacylglycerol/inositol-1,4,5-trisphosphate pathway (such as alpha 1-adrenergic, angiotensin II, and endothelin). In the non-failing human heart, however, activation of all these receptor systems induces only submaximal positive inotropic effects when compared with those caused by beta-adrenoceptor stimulation, indicating that in humans the cardiac beta-adrenoceptor-Gs-protein-adenylate cyclase pathway is the most powerful mechanism to increase heart rate and contractility. On the other hand, at least three receptor systems acting through inhibition of cAMP formation (Gi-protein coupled receptors) exist in the human heart: muscarinic M2-, adenosine A1-, and somatostatin-receptors. Activation of M2- and A1-receptors causes negative inotropic effects in the non-failing human heart: in atria activation of both receptors causes decreases in basal as well as in isoprenaline-stimulated force of contraction, but in ventricles only isoprenaline-stimulated force of contraction is depressed.
Basic Res Cardiol 1992
PMID:Receptor systems in the non-failing human heart. 135 55

Phospholipid metabolism is altered during ischemia and post-ischemic reperfusion. Past studies demonstrating elevated myocardial free fatty acid and lysophospholipid content infer accelerated phospholipid degradation involving phospholipase A activity. Recently, ischemic and post-ischemic reperfusion (reperfusion) have been shown to affect levels of phosphoinositide (PPI) degradation products. Considering the role of PPI turnover in regulation of cellular calcium homeostasis, our laboratory and others have suggested that alteration in the metabolism of the inositol phospholipids could play a role in the development of ischemia-induced calcium overload injury. Using an isolated rat heart model (Langendorff perfusion), this study examines the effect of global ischemia and reperfusion on ventricular phosphoinositide-specific phospholipase C (PLC) activity and PLA2 activity. The primary purpose was to determine if ischemia and reperfusion-induced changes in PLC activity could explain previously observed changes in PPI degradation products, and whether PLC and PLA2 activities were similarly or differentially altered by ischemia and reperfusion. PLC and PLA2 activities were measured in cytosolic and total membrane fractions from control (perfused), ischemic (5, 10, 30, and 60 min), and post-ischemic reperfused ventricular tissue. Phospholipase activity was determined under optimal in vitro conditions using exogenous radiolabeled substrates. Alterations in membrane-associated PPI-PLC activity correlated with reported ischemia and reperfusion-induced changes in ventricular content of PPI metabolites. Membrane PLC activity increased slightly at 5 min of ischemia, decreased significantly at 10 min of ischemia, and continued to decrease with longer duration of ischemia (73% of control after 60 min). Cytosolic PPI-PLC activity was decreased at 5 min, and then significantly increased by longer durations of ischemia, while cytosolic PLA2 activity was reduced at all time points. Pretreatment with muscarinic, alpha 1-adrenergic, beta-adrenergic, and adenosine receptor blockers did not alter ischemia-elicited changes in PLC activity. Reperfusion caused a 140% to 200% rise in the activities of all phospholipases in all fractions after 40 min of ischemia, but not after 10 min of ischemia. Results suggest 1) ischemia and reperfusion-elicited alterations in membrane-associated PPI-PLC activity can explain previously observed changes in phosphoinositide turnover metabolites, 2) cytosolic and membrane-associated PPI-PLC and PLA2 activities are not uniformly affected by ischemia, 3) reperfusion following ischemia of sufficient duration initiates uniform activation of PIP2-PLC and PLA2, and 4) because ischemia and reperfusion-induced changes in phospholipase activity can be detected under optimal in vitro assay conditions (removed from the in vivo ischemic microenvironment), it is likely that the enzymes themselves have been altered.
Basic Res Cardiol
PMID:Changes in phosphoinositide-specific phospholipase C and phospholipase A2 activity in ischemic and reperfused rat heart. 159 Jul 34

The combined action of phosphatidylcholine preferring phospholipase C (PC-PLC) and intracellular lipases has recently been shown to cause glycerol output in energy deprived rat cardiomyocytes. In the present study we examined the effect of hypothermia and rewarming on PC-PLC evoked glycerol output in freshly isolated, calcium-tolerant myocytes. The cells were preincubated for 60 min at hypothermic (5 degrees C) or normothermic (37 degrees C) conditions in Krebs-Henseleit bicarbonate buffer (pH 7.4) supplemented with 1 mM DL-carnitine, 1% B.S.A. and 5 mM glucose. Addition of PC-PLC resulted in a significantly higher (P less than 0.05) output of glycerol in myocytes undergoing rewarming than in myocytes kept constantly at 5 degrees C or 37 degrees C. The values obtained for PC-PLC induced glycerol output (difference in glycerol output between incubations with and without PC-PLC) were 6.77 +/- 2.6 (37 degrees C), 4.54 +/- 1.7 (5 degrees C) and 22.85 +/- 5.9 (5-37 degrees C) nmol/10(6) cells.h. Rewarming in addition caused a significantly higher (P less than 0.05) leakage of lactate dehydrogenase (LDH) from the rewarmed cells as compared to cells at constant temperatures (5 degrees C or 37 degrees C). However, there was no additional effect of PC-PLC on LDH leakage. The elevated PC-PLC induced glycerol output in rewarmed myocytes was not related to a fall in the percentage of rod-shaped cells or a reduced cellular content of ATP, since no differences could be detected between the various myocyte preparations with respect to these parameters.(ABSTRACT TRUNCATED AT 250 WORDS)
J Mol Cell Cardiol 1992 May
PMID:Effects of hypothermia and rewarming on phospholipase C-evoked glycerol output in rat myocardial cells. 163 71

The effects of chronic amiodarone therapy on myocardial phospholipid hydrolysis induced by total in vitro ischaemia were investigated in cat hearts. Chronic treatment of cats with amiodarone (30 mg/kg/day, orally) for 6 weeks resulted in a sufficient uptake of the drug reaching tissue levels of 83 +/- 13 & 122 +/- 22 microM (n = 12) for amiodarone and its principle metabolite, desethylamiodarone, respectively. This was accompanied by a significant increase (37%, P less than 0.001) in total phospholipid content of heart in treated as compared to untreated animals. Upon in vitro total ischaemia, these endogenous drug levels were sufficient to attenuate significantly hydrolysis of membrane phospholipid. The degree of attenuation was dependent upon the duration of ischaemic insult. In this regard, protection against phospholipid losses by amiodarone treatment was significantly more in the later irreversible phase of ischaemic injury whether studied in an in vitro total ischaemia model or in an isolated perfused heart preparation. Similar trend was observed in the relative accumulation of lysophospholipid and non-esterified fatty acid levels during ischaemia, i.e. both were significantly attenuated by amiodarone treatment. However, in contrast to the fatty acid data, the net changes in lysophospholipids per gram tissue wet weight were similar in treated and untreated animals, suggesting that the protective effects of amiodarone may have involved other enzymes including phospholipase C and D. Also, during the entire time course studied, all the phospholipid classes appeared to be affected to more or less a similar degree, indicating that the effects of the drug may have manifested in other subcellular compartments besides lysosomes. However, at all time periods studied, the net release of eicosatetraenoic and docosahexaenoic acid (fatty acids occupying primarily sn-2 position of phospholipids) was different, release of the former fatty acid being inhibited more than the latter, suggesting specific interaction of amiodarone with the molecular species of phospholipid. The data suggest that amiodarone attenuates ischaemia-induced membrane lipid abnormalities in part through modulation of phospholipid metabolism, and that this effect may be one of the key determinants which contribute to its antiarrhythmic properties during acute ischaemia.
J Mol Cell Cardiol 1992 May
PMID:Effect of amiodarone therapy on the time course of myocardial phospholipid hydrolysis during in vitro total ischaemia in cat hearts. 163 74

Although stimulated [3H] inositol phosphate turnover has been demonstrated in isolated, perfused [3H] inositol prelabelled rat hearts, there is still no information regarding Ins (1,4,5)P3 levels in intact cardiac muscle. Using a D-myo-Ins(1,4,5)P3 assay system, Ins(1,4,5)P3 levels were determined in isolated perfused rats hearts during ischaemia, reperfusion and alpha 1-adrenergic stimulation via noradrenaline (3 x 10(-5) M). Control hearts contained +/- 674 pmols Ins(1,4,5)P3/g dry heart weight. Myocardial Ins(1,4,5)P3 levels were significantly decreased (+/- 389 pmols/g dry heart weight) after exposure to 20 mins of normothermic ischaemic cardiac arrest (NICA). Reperfusion produced a marked increase in Ins(1,4,5,)P3 levels (+/- 1,115 pmols/g dry heart weight) after only 30 s. Noradrenaline caused a 3-4 fold increase in tissue Ins(1,4,5)P3 levels within 30 s. After 20 mins stimulation with noradrenaline, the Ins(1,4,5)P3 levels were still significantly elevated. The rise in tissue Ins(1,4,5)P3 levels during reperfusion as well as during noradrenaline administration was counteracted by neomycin (0.5 x 10(-3) M), an inhibitor of phosphoinositidase specific phospholipase C. In both events neomycin restored the Ins(1,4,5)P3 levels to control values. For correlation of tissue Ins(1,4,5)P3 levels with mechanical events, noradrenaline (3 x 10(-5) M), in the presence of 10 mM LiCl, 10(-7) M propranolol and 10(-7) M atropine, was administered to isolated perfused rat hearts and the mechanical performance recorded over a period of 20 mins. Noradrenaline caused a significant increase in peak systolic pressure and work performance which was maintained for at least 10 mins, suggesting that the positive inotropic effects of noradrenaline may be provoked by Ins(1,4,5)P3. Furthermore, the finding that 20 min NICA followed by 30 s reperfusion causes an immediate significant increase in Ins(1,4,5)P3 content suggests a role for the phosphatidylinositol pathway in the intracellular Ca2+ overloading, characteristic of ischaemia-reperfusion.
J Mol Cell Cardiol 1991 Jul
PMID:Increased myocardial inositol trisphosphate levels during alpha 1-adrenergic stimulation and reperfusion of ischaemic rat heart. 179 34

Thromboxane (Tx) A2 is a product of cyclooxygenase catalyzed metabolism of arachidonic acid. It is formed via prostaglandin (PG) endoperoxide intermediates (PGG2 and PGH2) by a specific synthase. PGH2 appears to exert the same biologic effects as TxA2. The cDNA for a TxA2 receptor has been cloned from a human placental library. Although pharmacologic and biochemical studies suggest the presence of multiple isoforms, this remains to be confirmed at the molecular level. A hydropathy plot of the deduced amino acid sequence of the available clone suggests that it has 7 transmembrane spanning domains, typical of a G protein linked receptor. Pharmacologic studies imply that Tx receptors in platelets are linked to phospholipase C activation via pertussis toxin insensitive G proteins. Candidates include the 42 kD Gq and the 60 kD Ge. TxA2 acts as an amplifying signal for platelet agonists and the response to this eicosanoid is tightly regulated. Mechanisms include rapid hydrolysis of the agonist to the inactive TxB2, autoinactivation of Tx synthase, rapid homologous TxA2 receptor desensitization due to receptor-G protein uncoupling, coincidental sensitization to counterregulatory Gs linked receptor systems and stimulation of prostacyclin formation by TxA2. Due to its role as an amplification signal in platelet activation, inhibition of Tx synthesis and action is an effective mechanism for preventing platelet-dependent vascular occlusion. Aspirin is of proven efficacy in this regard. Tx synthase inhibitors and antagonists are under clinical investigation.
Am J Cardiol 1991 Sep 03
PMID:Mechanisms of platelet activation: thromboxane A2 as an amplifying signal for other agonists. 189 57

The alpha 1-adrenergic receptor exists as at least two distinct subtypes, alpha 1a and alpha 1b. Based on hydrophobic exclusion studies and limited proteolysis of the cloned receptor, it appears to possess characteristics analogous to other membrane-bound receptors including seven membrane spanning domains, three extracellular, and three intracellular loops, with extensive glycosylation near the extracellular amino terminus. Although the receptor is coupled to phospholipase C in cardiac myocytes, with activation resulting in the production of inositol trisphosphate (IP3) and diacylglycerol, recent findings suggest that the receptor may also be linked to phospholipase A2, phospholipase D, and cyclic nucleotide phosphodiesterase. The alpha 1-adrenergic receptor has been shown to increase in response to myocardial ischemia in a number of different species and to mediate not only positive inotropic effects, but also to contribute substantially to arrhythmogenesis. The increase in alpha 1-adrenergic receptors can also occur in isolated adult ventricular myocytes in response to hypoxia, a mechanism which appears to be secondary to the sarcolemmal accumulation of long-chain acylcarnitines. This increase in alpha 1-adrenergic receptors in hypoxic myocytes is also linked to an enhanced increase in IP3 in response to receptor stimulation. These and other findings obtained in vivo during ischemia suggest that alpha 1-adrenergic mechanisms can become prominent in myocardium under pathophysiologic conditions in which a depressed contractile state exists and may therefore serve as a secondary inotropic system. However, the arrhythmogenic effects of stimulation of the alpha 1-adrenergic receptor in the ischemic heart in man may contribute substantially to arrhythmogenesis and, thereby, to the incidence of sudden cardiac death.
Basic Res Cardiol 1990
PMID:Modulation of alpha-adrenergic receptors and their intracellular coupling in the ischemic heart. 196 2

In chronic models of hypertension such as the spontaneously hypertensive rat (SHR), thickening of the media of large arteries occurs mainly through smooth muscle cell (SMC) hypertrophy accompanied by DNA replication resulting in large polyploid cells. In resistance vessels of SHR, medial hypertrophy occurs through a hyperplastic response. It has been suggested that this hyperplasia is due to mitogens such as platelet-derived growth factor (PDGF), while the hypertrophied polyploid cells occur from stimulation by angiotensin II from within the vessel wall. Angiotensin II activates many of the same cellular pathways as PDGF, including stimulation of phospholipase C, mobilization of intracellular calcium and activation of Na+/H+ exchange. Both induce transient increases in the proto-oncogenes c-fos and c-myc. However, a possible explanation for the difference in SMC response may be involvement of an intracellular pathway stimulated by PDGF (but not by angiotensin II), such as stimulation of JE (a cytokine-like molecule), which may activate transcriptional events necessary for mitogenesis. In atherosclerosis vascular hypertrophy occurs in the form of focal intimal thickening and results from hyperplasia of diploid SMC and their greatly increased production of extracellular matrix, (particularly collagen) and the accumulation of intra- and extracellular lipid. The SMC involved in atherogenesis are phenotypically modified compared with the SMC of undiseased regions, and amongst other features have a lower volume fraction of myofilaments (Vvmyo). Associated with modulation to a low Vvmyo are increases in SMC expression of mRNA for collagens type I (alpha 1 and alpha 2) and type III (alpha 1), elastin, fibronectin, as well as massive increases in collagen protein (26- to 45-fold), glycosaminoglycans (5-fold), and lipid accumulation (7-fold).(ABSTRACT TRUNCATED AT 250 WORDS)
Basic Res Cardiol 1991
PMID:Molecular biology of vascular hypertrophy. 203 94

The phosphoinositide-specific phospholipase C (PLC) activity present in the soluble and sarcolemmal enriched membrane fraction from guinea pig hearts was characterized using phosphatidyl [3H]inositol 4,5-biphosphate (PIP2) or phosphatidyl [3H]inositol 4-monophosphate (PIP) as substrates. The PLC activities (cytosolic and membrane associated) were specific for polyphosphoinositides (PIP2 and PIP) since no other phospholipids were hydrolyzed at pH 7.0 under various ionic conditions. Both enzymic activities were Ca2(+)-dependent (half maximal activities were achieved around pCa 5.0). The pH, detergent (deoxycholate), divalent (Ca2+ and Mg2+), and monovalent (Na+ and K+) cation dependencies were very similar between the cytosolic and membrane-associated enzyme activities, using either PIP2 or PIP as substrate. Hydrolysis of the polyphosphoinositides was inhibited in the presence of phosphatidylethanolamine, phosphatidylserine, or phosphatidylcholine. Under optimal conditions (pH 7.0, 1 mM Ca2+, 2.5 mM Mg2+, 100 mM Na+ and 0.07% deoxycholate) the specific activities of the cytosolic and membrane-associated enzymes were 19.9 +/- 0.9 and 10.1 +/- 0.9 nmol/min/mg protein, respectively, using PIP2 as substrate. Under the same conditions these activities were 18.1 +/- 1.0 and 8.0 +/- 0.8 nmol/min/mg protein for the cytosolic and membrane fractions, respectively, using PIP as substrate. Based on the similarity of the characteristics of these two PLC enzyme activities, it is suggested that the cytosolic and membrane-associated enzyme forms may be closely related.
Basic Res Cardiol
PMID:Characterization of cytoplasmic and membrane-associated phosphatidylinositol 4,5-biphosphate phospholipase C activities in guinea pig ventricles. 215 98


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