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A competitive inhibitor of phospholipase A2 decreases surfactant phosphatidylcholine degradation by the rat lung.

ABSTRACT: We have shown previously that radiolabelled phosphatidylcholine (PC) in liposomes or natural surfactant is removed from the alveolar space and metabolically recycled in a process that is stimulated by cyclic AMP (cAMP). In this study, we evaluated the effect of a transition-state phospholipid analogue (MJ33; 1-hexadecyl-3-trifluoroethylglycero-sn-2-phosphomethanol) that competitively inhibited acidic phospholipase A2 (PLA2) activity (pH 4.0) of lung homogenate by more than 97%, but had no effect on PLA2 activity at pH 8.5. MJ33 incorporated into unilamellar liposomes (dipalmitoyl PC/egg PC/cholesterol/phosphatidylglycerol, molar proportions 10:5:3:2) or co-sonicated with biosynthesized natural surfactant was instilled into the trachea of the anaesthetized rat; lungs were then removed for 2 h perfusion in the absence or presence of 0.1 mM-8-bromo cAMP. Total uptake for phospholipid was unchanged in the presence of the inhibitor MJ33. Degradation of labelled PC during 2 h perfusion in the absence of MJ33 was approx. 26% of that instilled for choline-labelled liposomal PC, 16% for liposomal PC labelled in the second fatty-acyl position, and 33% for choline-labelled natural surfactant. Degradation of PC was decreased by approx. 25-40% for each substrate in the presence of MJ33. Inhibition of lipid degradation depended on the mole fraction of MJ33 in the liposomes and was maximal at 1 mol%. These studies demonstrate a significant role for acidic Ca(2+)-independent PLA2 in the degradation of internalized alveolar PC, but further indicate that this enzyme accounts for a minor fraction of total lung PC metabolism.

SUBMITTER: Fisher AB

PROVIDER: S-EPMC1132025 | biostudies-other | 1992 Dec

REPOSITORIES: biostudies-other

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Enhanced Phospholipase A2 group 3 expression by oxidative stress decreases the insulin-degrading enzyme

Project description:Oxidative stress has a ubiquitous role in neurodegenerative diseases and oxidative damage in specific regions of the brain is associated with selective neurodegeneration. We previously reported that Alzheimer disease (AD) model mice showed decreased insulin-degrading enzyme (IDE) levels in the cerebrum and accelerated phenotypic features of AD when crossbred with alpha-tocopherol transfer protein knockout (Ttpa-/-) mice. To further investigate the role of chronic oxidative stress in AD pathophysiology, we performed DNA microarray analysis using young and aged wild-type mice and aged Ttpa-/- mice. Among the genes whose expression changed dramatically was Phospholipase A2 group 3 (Pla2g3); Pla2g3 was identified because of its expression profile of cerebral specific up-regulation by chronic oxidative stress in silico and in aged Ttpa-/- mice. Immunohistochemical studies also demonstrated that human astrocytic Pla2g3 expression was significantly increased in human AD brains compared with control brains. Moreover, transfection of HEK293 cells with human Pla2g3 decreased endogenous IDE expression in a dose-dependent manner. Our findings show a key role of Pla2g3 on the reduction of IDE, and suggest that cerebrum specific increase of Pla2g3 is involved in the initiation and/or progression of AD. Gene expression in cerebral cortex and cerebellum of mice were determined using Agilent chips. To ensure higher quality results in gene expression data, we conducted microarrays on 4 mice per group. Young mice were 2 months old and the other aged mice were 29 months old at the time of use. Data were standardized using global normalization and pro-cessed by R-program. An absolute fold change threshold of greater than 1.5 was required to be considered for further analyses. Expression values were in log2 scale.

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Enhanced Phospholipase A2 group 3 expression by oxidative stress decreases the insulin-degrading enzyme

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Enhanced Phospholipase A2 Group 3 Expression by Oxidative Stress Decreases the Insulin-Degrading Enzyme.

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Deficiency of phospholipase A2 group 7 decreases intestinal polyposis and colon tumorigenesis in Apc(Min/+) mice.

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Inhibition of lipoprotein-associated phospholipase A2 ameliorates inflammation and decreases atherosclerotic plaque formation in ApoE-deficient mice.

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