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Induction of glutathione synthesis by oxidized low-density lipoprotein and 1-palmitoyl-2-arachidonyl phosphatidylcholine: protection against quinone-mediated oxidative stress.

ABSTRACT: Exposure of endothelial cells to oxidized low-density lipoprotein (oxLDL) leads to diverse cellular effects, including induction of the intracellular antioxidant GSH. It is not known whether lipid-or protein-derived oxidation products cause GSH induction and whether this involves increased activity of the key enzyme in its synthesis, glutamate-cysteine ligase (GCL). Furthermore, the effect of oxLDL exposure on the cell's ability to combat oxidative stress has not been previously examined. In the present study we found that, in bovine aortic endothelial cells, LDL or 1-palmitoyl-2-arachidonyl phosphatidylcholine oxidized by different reactive oxygen and nitrogen species induced GSH synthesis. However, prevention of GSH synthesis during exposure to oxLDL caused extensive cell death. The mediator causing GSH induction was shown to be a polar lipid and resulted in the increased activity of GCL as well as increased protein levels of the regulatory subunit of GCL. Pretreatment with both oxLDL and the polar lipid subfraction of the oxLDL protected cells against the toxicity of 2,3-dimethoxynaphthoquinone (DMNQ), a superoxide- and H(2)O(2)-forming compound. The potential of a low level of lipid peroxidation products to initiate cytoprotective pathways are discussed.

SUBMITTER: Moellering DR

PROVIDER: S-EPMC1222359 | biostudies-other | 2002 Feb

REPOSITORIES: biostudies-other

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Time course-changes in phosphatidylcholine profile during oxidative modification of low-density lipoprotein.

Project description:BackgroundOxidized phosphatidylcholines (oxPC) and lysophosphatidylcholine (lysoPC) generated during the formation of oxidized low-density lipoprotein (oxLDL) are involved in atherosclerotic lesion development. We investigated the time course-changes in phosphatidylcholine (PC) molecular species during oxidation of LDL to determine how those atherogenic PCs are produced.MethodsHuman and rabbit LDLs were pretreated with or without a selective platelet-activating factor acetylhydrolase (PAF-AH) inhibitor. LDL was oxidized by incubation with copper sulfate, and PC profiles were analyzed by liquid chromatography-tandem mass spectrometry.ResultsWhen human LDL was oxidized, the peak areas for polyunsaturated fatty acid (PUFA)-containing PC species dramatically decreased after a short lag period, concomitantly lysoPC species increased sharply. Although a variety of oxPC species containing oxidized fatty acyl groups or cleaved acyl chains are formed during LDL oxidation, only a few oxPC products accumulated in oxLDL: 1-palmitoyl-2-(9-oxo-nonanoyl) PC and long-chain oxPC with two double bonds. Pretreatment of LDL with the PAF-AH inhibitor greatly reduced lysoPC production while it had no effect on lipid peroxidation reactions and oxPC profiles. Rabbit LDL, which has a different composition of PC molecular species and needs a longer time to reach achieve full oxidation than human LDL, also accumulated lysoPC during oxidation. The increase in lysoPC in rabbit oxLDL was suppressed by pretreatment with the PAF-AH inhibitor. The major oxPC species formed in rabbit oxLDL were almost the same as human oxLDL.ConclusionsThese results suggest that lysoPC species are the major products and PAF-AH activity is crucial for lysoPC generation during oxidation of LDL. The oxPC species accumulated are limited when LDL is oxidized with copper ion in vitro.

| S-EPMC4007754 | biostudies-literature

Non-oxidative modification of native low-density lipoprotein by oxidized low-density lipoprotein.

Project description:The oxidative modification of low-density lipoprotein (LDL) has been implicated in the pathogenesis of atherosclerosis, although little is known as yet about the precise mechanism of oxidation in vivo. The studies presented here demonstrate that, in the absence of cells or transition metals, oxidized LDL can modify native LDL through co-incubation in vitro such as to increase its net negative charge, in a concentration-dependent manner. The interaction is not inhibited by peroxyl radical scavengers or metal chelators, precluding the possibility that the modification of native LDL by oxidized LDL is through an oxidative process. Studies with radioiodinated oxidized LDL showed no transfer of radioactivity to the native LDL, demonstrating that fragmentation of protein and the transfer of some of the fragments does not account for the modified charge on the native LDL particle. The adjacency of native to oxidized LDL in the arterial wall may be a potential mechanism by which the altered recognition properties of the apolipoprotein B-100 may arise rapidly without oxidation or extensive modification of the native LDL lipid itself.

| S-EPMC1217359 | biostudies-other

Resveratrol Confers Vascular Protection by Suppressing TLR4/Syk/NLRP3 Signaling in Oxidized Low-Density Lipoprotein-Activated Platelets.

Project description:This study investigated the effect of resveratrol on Toll-like receptor 4- (TLR4-) mediated matrix metalloproteinase 3 (MMP3) and MMP9 expression in oxidized low-density lipoprotein- (ox-LDL-) activated platelets and the potential molecule mechanism. Human platelets were used in the present study. The results showed that resveratrol suppressed TLR4, MMP3, and MMP9 expression in ox-LDL-activated platelets. The TLR4 inhibitor CLI-095 also inhibited MMP3 and MMP9 expression and secretion in ox-LDL- and lipopolysaccharide- (LPS-) activated platelets. The combination of resveratrol and CLI-095 synergistically suppressed MMP3 and MMP9 expression in ox-LDL- and LPS-activated platelets. These findings suggest that the resveratrol-induced inhibition of MMP3 and MMP9 expression is linked to the suppression of TLR4 activation. Resveratrol also suppressed spleen tyrosine kinase (Syk) phosphorylation and nucleotide-binding domain leucine-rich repeat containing protein 3 (NLRP3) expression and IL-1β secretion in ox-LDL- and LPS-treated platelets. The coimmunoprecipitation results showed that resveratrol inhibited the binding of Syk and NLRP3. Finally, resveratrol reduced vascular senescence cells and the expression of TLR4, MMP3, and MMP9 and prevented alterations of vascular structure in 52-week-old mice. Our findings demonstrated that resveratrol decreased inflammatory protein expression and improved vascular structure in aged mice. Resveratrol inhibited the expression of TLR4 and secretion of MMP3, MMP9, and IL-1β. The mechanism of action of resveratrol appears to be associated with the inhibition of TLR4/Syk/NLRP3 activation in ox-LDL-activated platelets.

| S-EPMC7935581 | biostudies-literature

Oxidized Low-Density Lipoprotein Promotes In Vitro Calcification.

Project description:Calcification plays an important role in the human body in maintaining homeostasis. In the human body, the presence of a high amount of oxidized low-density lipoprotein (ox-LDL) is a consistent feature of the local areas that are common sites of ectopic calcification, namely dental calculus, renal calculus, and the areas affected by arteriosclerosis. Hence, ox-LDL may have some effect on calcification. Scanning electron microscopy (SEM) observation revealed a high amount of amorphous calcium phosphate (ACP) when ox-LDL was included in the solution. In the in vitro experiment, the highest amount of precipitation of calcium phosphate was observed in the solution containing ox-LDL compared to the inclusion of other biomaterials and was 4.2 times higher than that of deionized water for 4.86 mM calcium and 2.71 mM phosphate. The morphology of calcium phosphate precipitates in the solution containing ox-LDL differed from that of the precipitates in solutions containing other biomaterials, as determined by transmission electron microscopy (TEM). Through the time course observation of the sediments using TEM, it was observed that the sediments changed from spherical or oval shape to a thin film shape. These results indicate that sediments acquired a long-range order array, and the phase transitioned from non-crystalline to crystalline with an increased time and density of ACP. Thus, it is concluded that ox-LDL promoted ACP precipitation and it plays an important role in ectopic calcification.

| S-EPMC7697660 | biostudies-literature

Oxidized Low-Density Lipoprotein drives dysfunction of the liver lymphatic system

Project description:Single-cell RNA-sequencing revealed that the transcriptional profile of LECs from HFHC livers was consistent with changes in the LEC transcriptome that reflect both proliferation and a potential de-differentiation of liver LECs in the context of disease which may impact their functions, such as permeability and metabolism.

2021-08-28 | GSE157054 | GEO

Treatment of macrophages with oxidized low-density lipoprotein increases their intracellular glutathione content.

Project description:Macrophages derived from the human monocyte cell line THP-1 or isolated from the peritoneum of C3H/HEJ mice were incubated with oxidized low-density lipoprotein (LDL) and the total glutathione content (oxidized plus reduced) was measured. An initial depletion of glutathione was followed by an increase, such that after a period of 24 h the glutathione content has approximately doubled. This response required the oxidation of the lipid phase of the LDL molecule, since both native LDL and acetylated LDL had little effect on glutathione levels. The response of the cells to oxidized LDL was dependent on the extent of oxidative modification of the protein. It was also found that 4-hydroxynonenal had a similar effect on THP-1 cells, and we suggest that this or other aldehydes present in oxidized LDL causes the induction of glutathione synthesis in response to an initial oxidative stress and consequent glutathione depletion. In addition, we found that both cell types possess transferases and peroxidases capable of detoxifying aldehydes and peroxides. However, treatment of cells with oxidized LDL or 4-hydroxynonenal for a period of 24 h had no effect on the activities of these enzymes.

| S-EPMC1151361 | biostudies-other

Attenuated suppression of the oxidative burst by cells dying in the presence of oxidized low density lipoprotein.

Project description:Macrophages ingesting apoptotic cells attenuate inflammatory responses, such as reactive oxygen species (ROS) generation. In atherosclerosis, ongoing inflammation and accumulation of apoptotic/necrotic material are observed, suggesting defects of phagocytes in recognizing or responding to dying cells. Modified lipoproteins such as oxidized LDL (oxLDL) are known to promote inflammation and to interfere with apoptotic cell clearance. Here, we studied the impact of cells exposed to oxLDL on their ability to interfere with the oxidative burst in phagocytes. In contrast to apoptotic cells, cells dying in response to or in the presence of oxLDL failed to suppress ROS generation despite efficiently being taken up by phagocytes. In addition, apoptotic cells, but not oxLDL-treated cells, inhibited phosphorylation of extracellular signal-regulated kinase, which is important for NADPH oxidase activation. oxLDL treatment did not interfere with activation of the antiinflammatory transcriptional regulator peroxisome proliferator-activated receptor gamma by apoptotic cells. Moreover, cells exposed to oxLDL failed to suppress lipopolysaccharide- induced proinflammatory cytokine expression, whereas apoptotic cells attenuated these phagocyte responses. Thus, the presence of oxLDL during cell death impaired the ability of apoptotic cells to act antiinflammatory with regard to oxidative burst inhibition and cytokine expression in phagocytes.

| S-EPMC2759823 | biostudies-literature

The Application of a Modified d-ROMs Test for Measurement of Oxidative Stress and Oxidized High-Density Lipoprotein.

Project description:Reactive oxygen species (ROS) are involved in the initiation and progression of atherosclerosis. ROS-derived hydroperoxides, as an indicator of ROS production, have been measured by using the diacron reactive oxygen metabolites (d-ROMs) test, which requires iron-containing transferrin in the reaction mixture. In this study we developed a modified d-ROMs test, termed the Fe-ROMs test, where iron ions were exogenously added to the reaction mixture. This modification is expected to exclude the assay variation that comes from different blood iron levels in individuals. In addition, this Fe-ROMs test was helpful for determining the class of plasma lipoproteins that are hydroperoxidized. Low-density lipoprotein/very low-density lipoprotein (LDL/VLDL) and high-density lipoprotein (HDL) were purified by use of an LDL/VLDL purification kit and the dextran sulfate-Mg2+ precipitation method, respectively; their hydroperoxide contents were assessed by performing the Fe-ROMs test. The majority of the hydroperoxides were detected only in the HDL fraction, not in the LDL/VLDL. Further detailed analysis of HDLs by size-exclusion high-performance liquid chromatography revealed that the hydroperoxide-containing molecules were small-sized HDLs. Because HDL was shown to be the principal vehicle for the plasma hydroperoxides, this Fe-ROMs test is a beneficial method for the assessment of oxidized-HDL levels. Indeed, Fe-ROMs levels were strongly associated with the levels of oxidized HDL, which were determined by performing the malondialdehyde-modified HDL enzyme immunoassay. In conclusion, the Fe-ROMs test using plasma itself or the HDL fraction after dextran sulfate-Mg2+ precipitation is useful to assess the functionality of HDL, because the oxidation of HDL impairs its antiatherogenic capacity.

| S-EPMC5343988 | biostudies-literature

Relationship of lipoprotein-associated phospholipase A2 and oxidized low density lipoprotein in carotid atherosclerosis.

Project description:Plasma levels of lipoprotein-associated phospholipase A(2) (Lp-PLA(2)) and oxidized low density lipoprotein (oxLDL) have been identified as risk factors for cardiovascular disease. Lp-PLA(2) is the sole enzyme responsible for the hydrolysis of oxidized phospholipids on LDL particles in atherosclerotic plaques. We have studied the relationship between Lp-PLA(2) and oxLDL in carotid endarterectomy (CEA) tissues and in matched plasmas. In extracts from CEA anatomical segments, the levels of oxLDL were significantly associated with the levels of Lp-PLA(2) protein (r = 0.497) and activity (r = 0.615). OxLDL and Lp-PLA(2) mass/activity were most abundant in the carotid bifurcation and internal segments where plaque was most abundant. In extracts from CEA atheroma, the levels of oxLDL and Lp-PLA(2) were significantly correlated (r = 0.634). In matched plasma and atheroma extracts, the levels of Lp-PLA(2) were negatively correlated (r = - 0.578). The ratio of Lp-PLA(2) to oxLDL was higher in atheromatous tissue (277:1) than in normal tissue (135:1) and plasma (13:1). Immunohistochemical experiments indicated that in plaques, oxLDL and Lp-PLA(2) existed in overlapping but distinctly different distribution. Fluorescence microscopy showed both oxLDL and Lp-PLA(2) epitopes on the same LDL particle in plasma but not in plaque. These results suggest that the relationship between Lp-PLA(2) and oxLDL in the atherosclerotic plaque is different from that in the plasma compartment.

| S-EPMC2724786 | biostudies-literature

Expression profiles of microRNAs in oxidized low-density lipoprotein-stimulated RAW 264.7 cells

Project description:Foam cells were one of the hallmarks of atherosclerosis, and microRNAs (miRNAs) played an important role in the formation of foam cells. In order to explore the roles of miRNA in the formation of foam cells, In the present study, to understand the molecular mechanisms of miRNAs involved in AS, we provide insights into the genome-wide dynamic profiles of miRNAs by using high-throughput sequencing technology.

2019-06-05 | GSE99685 | GEO

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