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:3.1.1.34 (lipoprotein lipase)
7,025 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We observed a contractile action of ethanol (20-500 mM) and other alcohols (methanol and propanol, but not butanol) in guinea pig gastric longitudinal (LM) and circular (CM) smooth muscle preparations. The potency order for the alcohols in the LM preparation was: ethanol = propanol > methanol; and in the CM preparation, propanol > ethanol > methanol. Like epidermal growth factor-urogastrone (EGF), the contractile actions of ethanol in the LM and CM preparations required extracellular calcium and were blocked by the tyrosine kinase inhibitors, genistein and tyrphostin-47 (AG213). The tyrosine phosphatase inhibitor, pervanadate, potentiated the contractile action of ethanol in the LM preparation. Ethanol-induced contractions in both preparations were not affected by 4-methyl pyrazole, an inhibitor of alcohol dehydrogenase, and were unaffected by tetrodotoxin, atropine, prazosine or yohimbine. In the LM preparation, like EGF, the contractile action of ethanol was blocked by the cyclooxygenase inhibitor, indomethacin, and the diacylglycerol lipase inhibitor, U57,908; in the CM preparation, contractions caused by ethanol and EGF were still observed in the presence of these two inhibitors. Contractions caused by ethanol and EGF in the LM preparation were not affected by the epoxygenase inhibitor, ketoconazole; the lipoxygenase inhibitor, nordihydroguaiaretic acid; or the phospholipase A2 inhibitor, mepacrine. In contrast, in the LM preparation, EGF-induced contractions were attentuated by the EGF receptor-kinase inhibitor, PD153035; the MAP-kinase-kinase (MEK) inhibitor, PD98059; the kinase C inhibitor, GF109203X; and the phosphatidylinositol 3'-kinase inhibitors, Wortmannin and LY294002; whereas ethanol-induced contractions were unaffected by these inhibitors. Both ethanol and EGF caused small increases in the phosphotyrosyl protein content of the gastric tissue. We conclude that ethanol causes its contractile effects in the distinct gastric LM and CM preparations independent of nerve-released agonists and via a tyrosine kinase inhibitor-sensitive signal pathway that is in many respects similar to, but distinct from the one activated by EGF.
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PMID:Contractile action of ethanol in guinea pig gastric smooth muscle: inhibition by tyrosine kinase inhibitors and comparison with the contractile action of epidermal growth factor-urogastrone. 922 91

We have investigated the possible interaction (cross talk) between the phospholipase A2 (PLA2) and inositol 1,4,5-trisphosphate/protein kinase C (PKC) signaling pathways in rat lactotroph-enriched cell cultures. Melittin, a bee venom peptide, stimulated release of [3H]arachidonic acid ([3H]AA) from [3H]AA-labeled enriched lactotrophs in a dose-dependent manner. Moreover, melittin and exogenous AA induced a redistribution of PKC catalytic activity and PKC alpha and beta immunoreactivity from the soluble to the particulate fraction in resting and substance P (SP)-stimulated cells. Melittin had no effect on phospholipase C (PLC) activity. Pretreatment of cell cultures with the PLA2 inhibitors quinacrine and aristolochic acid resulted in a dose-dependent inhibition of melittin-stimulated PKC isozyme translocation as did the inhibitor of lipoxygenase, nordihydroguaiaretic acid, whereas the cyclooxygenase inhibitor indomethacin had no effect. SP and the phorbol ester 12-O-tetradecanoylphorbol 13-acetate (TPA) dose-dependently increased levels of [3H]AA released from cells. Pretreatment of cell cultures with quinacrine reduced the effect of SP on [3H]AA formation. After long-term treatment (24 h) of cells with TPA, the effect of TPA on [3H]AA production was not different from control, whereas SP still displayed [3H]AA-releasing abilities although not at full scale. Pretreatment of cells with thapsigargin, U 73122, methoxyverapamil, and RHC 80267, an inhibitor of diacylglycerol lipase, all resulted in reduced SP-stimulated [3H]AA liberation. Treatment of cell cultures with pertussis toxin (PTX) reduced the release of [3H]AA induced by SP, whereas PTX had no effect on SP-stimulated generation of 3H-inositol phosphates. On the basis of these results, it is concluded that (1) the PLA2 pathways interfere with the phosphoinositide-PLC signaling system at the level of PKC isozymes alpha and beta, the product responsible for this interaction being either AA or a metabolite produced by the action of lipoxygenase; (2) SP and TPA are able to activate the PLA2 pathway at a level at or beyond PLA2, and this effect is mediated, in part, through PKC alpha and beta species and (for SP) intracellular Ca2+ recruited from internal stores as well as from external sources; and (3) SP also activates PLA2 through a PTX-sensitive pathway distinct from the one coupled to phosphoinositide-PLC, which is PTX insensitive.
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PMID:Cross talk between substance P and melittin-activated cellular signaling pathways in rat lactotroph-enriched cell cultures. 923 37

We have recently demonstrated the presence of phospholipase A2 (PLA2) activity in cells from bovine retinal pigment epithelium (RPE) [Jacob et al. (1996) J. Biol. Chem. 271, 19209-19218]. We report here our results on the characterization of this RPE-PLA2 activity. We show that RPE probably contains two types of PLA2 enzyme, as indicated by the results obtained with different PLA2-active fractions eluted from cation-exchange columns and treated with Ca2+/EGTA, dithiothreitol, p-bromophenacyl bromide or heat. These results, in addition to those from PLA2 assays using different substrates, also suggest that RPE-PLA2 enzymes are different from the well-known secretory, cytoplasmic and Ca2+-independent forms. Sequential extraction of RPE with (1) isotonic, (2) hypertonic and (3) detergent-containing PBS argues for the presence of weakly membrane-associated enzymes. Control experiments using 'back and forth' TLC allowed us to discriminate between PLA2 and phospholipase C/diacylglycerol lipase activity and confirmed that, in our assay conditions, the release of fatty acids was indeed due to PLA2 enzymes. These results, together with those obtained by treating RPE homogenates with H2SO4, guanosine 5'-[gamma-thio]triphosphate, ATP and different protease inhibitors, permitted us to make the first characterization of these RPE-PLA2 enzymes. We conclude that RPE contains novel types of PLA2 that are different from the secretory, cytoplasmic and Ca2+-independent forms.
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PMID:Bovine retinal pigment epithelium contains novel types of phospholipase A2. 935 16

This study was conducted to determine the mechanism of arachidonic acid (AA) release elicited by phenylephrine (PHE) stimulation of alpha adrenergic receptor (AR), and its modulation by cyclic adenosine 3',5'-monophosphate (cAMP) in Rat-1 fibroblasts (R-1Fs) transfected with the alpha-1A, alpha-1B or alpha-1D AR. PHE increased AA release and also caused a marked accumulation of cAMP in R-1Fs expressing the alpha-1 AR subtypes, but not in those transfected with vector alone. PHE also enhanced phospholipase D (PLD), but not phospholipase A2 (PLA2) activity. The increase in PHE-induced AA release, PLD activity and cAMP accumulation differed among the various alpha AR subtypes with: alpha-1A > alpha-1B > alpha-1D AR. The effect of PHE to increase AA release was attenuated by C2-ceramide, an inhibitor of PLD; propranolol, a phosphatidate phosphohydrolase inhibitor; and RHC-80267, a diacylglycerol lipase inhibitor in R-1Fs expressing the alpha-1A AR. Forskolin, which activates adenylyl cyclase, increased cAMP accumulation and inhibited PHE-induced AA release and PLD activity in alpha-1A-AR-expressing R-1Fs. 8-(4-chlorophenyl-thio)-cAMP, a nonhydrolyzable analog of cAMP, also attenuated the rise in AA release and PLD activity elicited by PHE in these cells. In contrast, SQ 22536, an adenylyl cyclase inhibitor, and KT 5720, a protein kinase A inhibitor, increased PHE-induced AA release and PLD activity in R-1Fs expressing the alpha-1A AR. These data suggest that the alpha-1A, alpha-1B and alpha-1D ARs are coupled to PLD activation and cAMP accumulation. Moreover, PHE promotes AA release in R-1Fs expressing the alpha-1A AR through PLD activation. Furthermore, cAMP generated by alpha-1A AR stimulation acts as an inhibitory modulator of PLD activity and AA release via protein kinase A.
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PMID:Alpha-1A adrenergic receptor stimulation with phenylephrine promotes arachidonic acid release by activation of phospholipase D in rat-1 fibroblasts: inhibition by protein kinase A. 945

In previous studies, we have shown that mouse RAW 264.7 macrophages possess pyrimidinoceptors, coupled to a phosphoinositide-specific phospholipase C, with a higher specificity for UTP than for ATP. In the current study, we explored the mechanism involved in the UTP-induced intracellular acidification seen in this cell line. UTP (30 microM) caused a reversible pHi decrease of 0.16 +/- 0.01 unit; this effect was not influenced by the removal of extracellular Cl- or Na+ ions or by pretreatment with 5-(N-ethyl-N-isopropyl)-amiloride (10 microM), 5-nitro-2-(3-phenylpropylamino)benzoic acid (100 microM), staurosporine (1 microM), or Ro 31-8220 (1 microM) but was completely abolished by the removal of extracellular Ca2+. UTP (30 microM), thapsigargin (1 microM), and ionomycin (1 microM) each induced a similar extent of external Ca2+-dependent acidification with a similar time-dependency, but the effects were nonadditive. To further investigate the Ca2+-dependent mechanism, we studied the involvement of arachidonic acid (AA) and eicosanoid metabolites. The addition of AA (10 microM) but not arachidic acid (100 microM) produced a reduction in pHi. UTP, thapsigargin, and ionomycin induced Ca2+-dependent AA release. Furthermore, 4-bromo-phenacyl bromide [30 microM, a phospholipase A2 (PLA2) inhibitor-, nordihydroguaiaretic acid (50 microM, a lipoxygenase inhibitor), and MK-886 (10 microM, a 5-lipoxygenase-activating protein inhibitor) abolished the UTP- or ionomycin-induced responses, whereas indomethacin (30 microM, a cyclooxygenase inhibitor) and baicalein (10 microM, a selective 12-lipoxygenase inhibitor) had no effect. MAFP (a cPLA2 inhibitor) and REV 5901 (a 5-lipoxygenase inhibitor as well as a competitive antagonist of peptide leukotrienes), but not RHC 80267 (a diacylglycerol lipase inhibitor), also inhibited the UTP-induced response. In contrast, the pHi response to AA was unaffected by the presence of 4-bromo-phenacyl bromide or the removal of extracellular Ca2+ ions but abolished by addition of NDGA. Exogenous 5-hydroperoxyeicosatetraenoic acid (2 microM) also produced marked acidification, and UTP and ionomycin both induced peptide leukotriene formation. In conclusion, this is the first report indicating that lipoxygenase metabolites act as mediators of the Ca2+-dependent acidification seen in macrophages in response to UTP or ionomycin via activation of cPLA2 and AA release.
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PMID:Lipoxygenase metabolites as mediators of UTP-induced intracellular acidification in mouse RAW 264.7 macrophages. 946 90

Lipoprotein(a), Lp(a), is found in the extracellular matrix in atherosclerotic plaques, but with a different localization than LDL. A two-compartment system, with a monolayer of endothelial cells forming a barrier, was used to compare the transport, cell binding, and retention of Lp(a) and LDL into the subendothelial matrix. Baseline values for transport and retention of Lp(a) and LDL were not significantly different. Incubation with lipoprotein lipase or sphingomyelinase caused modest and similar increases in transport and retention of the two lipoproteins. In contrast, incubation with phospholipase A2 (PLA2) resulted in a marked (4-fold) increase in retention of Lp(a) on the subendothelial matrix, but a lesser (2-fold) increase in LDL retention. Moreover, PLA2 treatment of Lp(a) enhanced its binding to individual matrix proteins (fibronectin, laminin, or collagen) by 4-10 times above that of LDL. The enzymatic activity of PLA2 was responsible for its effect on Lp(a) binding. The lysine binding sites of Lp(a) contributed to the increased binding of PLA2-modified Lp(a) to the matrix, and the enhanced lysine binding functions of PLA2-modified Lp(a) was demonstrated by two independent approaches. Thus, PLA2 modification leads to enhanced interactions of lipoproteins with the extracellular matrix, and this effect is more pronounced with Lp(a).
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PMID:Phospholipase A2 modification enhances lipoprotein(a) binding to the subendothelial matrix. 953 Oct 56

The mechanism of agonist-activated arachidonate release was studied in segments of rat tail artery. Tail artery segments were prelabeled with [3H]arachidonate and then stimulated with norepinephrine (NE), and the radioactivity of the extracellular medium was determined. NE stimulated arachidonate release from the tissue without increasing arachidonic acid levels within cellular cytosol or crude membranes. About 90% of the extracellular radioactivity was shown to be unmetabolized arachidonate by TLC. Arachidonic acid release was not inhibited by the removal of the endothelium from the artery. NE exerted a half-maximal effect at a concentration of 0.2 microM. NE-stimulated arachidonate release was not inhibited by blockers of phospholipase C (U-73122), diacylglycerol lipase (RHC-80267), secretory phospholipase A2 (manoalide), calcium-insensitive phospholipase A2 (HELSS), or beta-adrenergic receptors (propranolol). NE-stimulated arachidonic acid release was inhibited by blockers of cytosolic phospholipase A2 (cPLA2) (AACOCF3), alpha 1-adrenergic receptors (prazosin), and specific G proteins (pertussis toxin). This indicated that NE stimulated arachidonate release from vascular smooth muscle via activation of alpha-adrenergic receptors, either Gi or Go, and cPLA2. NE-activated arachidonic acid release from vascular smooth muscle may play a role in force generation by the tissue. Perhaps arachidonic acid extends the effect of NE on one specific smooth muscle cell to its nearby neighbor cells.
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PMID:Norepinephrine stimulates arachidonic acid release from vascular smooth muscle via activation of cPLA2. 957 10

The pathogenicity of lipoprotein(a) [Lp(a)] as a risk factor for cardiovascular disease may depend upon its lysine binding sites (LBS) which impart unique functions to Lp(a) not shared with low density lipoprotein. Biologically relevant modifications of Lp(a) were tested for alterations of LBS activity using two previously described functional assays, a LBS-Lp(a) immunoassay and a lysine-Sepharose bead assay. In the LBS-Lp(a) immunoassay, minimal changes in the LBS activity of Lp(a) were observed after modification with lipoprotein lipase, sphingomyelinase, or phospholipase C. In contrast, a significant (p<0.003) increase in the LBS activity of Lp(a) occurred after phospholipase A2 (PLA2) treatment, and this increase was confirmed using the lysine-Sepharose bead assay. The increase depended upon the release of fatty acids from Lp(a) by PLA2. A decrease in the LBS activity of Lp(a) occurred after oxidation of Lp(a) with 2,2'-azobis(2-amidinopropane) dihydrochloride (AAPH) (44% decrease), but CuSO4 oxidation increased LBS activity (210%). N-acetylcysteine (NAC) treatment of Lp(a) decreased (48%) LBS activity while homocysteine treatment had no (89%) effect. Thus, modification of phospholipids and protein moieties can alter the LBS-activity of Lp(a). Such enzymatic and chemical modifications may contribute to the variability in LBS function of Lp(a) seen within the population.
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PMID:Enzymatic and chemical modifications of lipoprotein(a) selectively alter its lysine-binding functions. 959 30

The oxidation of low-density lipoprotein (LDL) is thought to contribute to atherogenesis. 15-Lipoxygenase (15LO) induces LDL oxidation, and phospholipase A2 enhances this process [Sparrow, C. P. , Parthasarathy, S., and Steinberg, D. (1988) J. LipidRes. 29, 745-753]. As the underlying mechanism of the enhancing effect has not been investigated previously, we here show that in the presence of soybean 15LO (SLO) or human 15LO (rhLO), the addition of lipoprotein lipase, porcine pancreatic, or human type IIa secretory phospholipase A2 (sPLA2) greatly enhanced the accumulation of hydro(pero)xides of all major classes of LDL's lipids. Hydroperoxides of free fatty acids accumulated exclusively as enzymic products with kinetics reflecting both the formation of free fatty acids and the initial 'build-up' of alpha-tocopheroxyl radical. In contrast, hydroperoxides of cholesteryl esters and phosphatidylcholine accumulated linearly over comparatively longer periods of time and, in the case of rhLO, well beyond inactivation of the oxygenase. With SLO, formation of oxidized esterified lipids occurred nonenzymically, independent of the presence of lipase and despite the oxygenase remaining active until the end of the incubation. Enhancement of rhLO-induced LDL lipid peroxidation by sPLA2 was eliminated by a neutralizing anti-sPLA2 antibody, indicating that lipolytic activity was required for this effect. LDL depleted of alpha-tocopherol was resistant to oxidation by 15LO alone, whereas lipase overcame this resistance, demonstrating that lipases enhance 15LO-induced enzymic and nonenzymic peroxidation of LDL lipids. This is likely due to provision of free fatty acid substrate, resulting in an enhanced rate of free radical formation which itself causes nonenzymic peroxidation of esterified lipids. As lipases and 15LO are present in atherosclerotic lesions, our findings could be of pathophysiological significance.
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PMID:Secretory phospholipase A2 and lipoprotein lipase enhance 15-lipoxygenase-induced enzymic and nonenzymic lipid peroxidation in low-density lipoproteins. 963 68

1. Polyunsaturated fatty acids are essential for normal cell membrane functioning because many membrane properties, such as fluidity and permeability, are closely related to the presence of unsaturated and polyunsaturated side chains. Lipid peroxidation results in loss of membrane polyunsaturated fatty acids and oxidized phospholipids as polar species contributing to increased membrane rigidity. 2. Polyunsaturated fatty acids are released from membrane phospholipids by a number of enzymic mechanisms involving the receptor-mediated stimulation of phospholipase A2 and phospholipase C/diacylglycerol lipase pathways. 3. The overstimulation of excitatory amino acid (EAA) receptors stimulates the activities of lipases and phospholipases, and this stimulation produces changes in membrane phospholipid composition, permeability, and fluidity, thus decreasing the integrity of plasma membranes. 4. Alterations in properties of plasma membranes may be responsible for the degeneration of neurons seen in neurodegenerative diseases. Two major processes may be involved in neuronal injury caused by the overstimulation of EAA receptors. One is a large Ca2+ influx and the other is an accumulation of free radicals and lipid peroxides as a result of neural membrane phospholipid degradation. It is suggested that calcium and free radicals act in concert to induce neuronal injury in acute trauma (ischemia and spinal cord injury) and in neurodegenerative diseases.
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PMID:Lipid peroxides in the free radical pathophysiology of brain diseases. 987 68


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