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Oxidized Lipoprotein as a Major Vessel Cell Proliferator in Oxidized Human Serum.

ABSTRACT: Oxidative stress is correlated with the incidence of several diseases such as atherosclerosis and cancer, and oxidized biomolecules have been determined as biomarkers of oxidative stress; however, the detailed molecular relationship between generated oxidation products and the promotion of diseases has not been fully elucidated. In the present study, to clarify the role of serum oxidation products in vessel cell proliferation, which is related to the incidence of atherosclerosis and cancer, the major vessel cell proliferator in oxidized human serum was investigated. Oxidized human serum was prepared by free radical exposure, separated using gel chromatography, and then each fraction was added to several kinds of vessel cells including endothelial cells and smooth muscle cells. It was found that a high molecular weight fraction in oxidized human serum specifically induced vessel cell proliferation. Oxidized lipids were contained in this high molecular weight fraction, while cell proliferation activity was not observed in oxidized lipoprotein-deficient serum. Oxidized low-density lipoproteins induced vessel cell proliferation in a concentration-dependent manner. Taken together, these results indicate that oxidized lipoproteins containing lipid oxidation products function as a major vessel cell proliferator in oxidized human serum. These findings strongly indicate the relevance of determination of oxidized lipoproteins and lipid oxidation products in the diagnosis of vessel cell proliferation-related diseases such as atherosclerosis and cancer.

SUBMITTER: Saito Y

PROVIDER: S-EPMC4970716 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Human serum amyloid A3 (SAA3) protein, expressed as a fusion protein with SAA2, binds the oxidized low density lipoprotein receptor.

Project description:Serum amyloid A3 (SAA3) possesses characteristics distinct from the other serum amyloid A isoforms, SAA1, SAA2, and SAA4. High density lipoprotein contains the latter three isoforms, but not SAA3. The expression of mouse SAA3 (mSAA3) is known to be up-regulated extrahepatically in inflammatory responses, and acts as an endogenous ligand for the toll-like receptor 4/MD-2 complex. We previously reported that mSAA3 plays an important role in facilitating tumor metastasis by attracting circulating tumor cells and enhancing hyperpermeability in the lungs. On the other hand, human SAA3 (hSAA3) has long been regarded as a pseudogene, which is in contrast to the abundant expression levels of the other isoforms. Although the nucleotide sequence of hSAA3 is very similar to that of the other SAAs, a single oligonucleotide insertion in exon 2 causes a frame-shift to generate a unique amino acid sequence. In the present study, we identified that hSAA3 was transcribed in the hSAA2-SAA3 fusion transcripts of several human cell lines. In the fusion transcript, hSAA2 exon 3 was connected to hSAA3 exon 1 or hSAA3 exon 2, located approximately 130kb downstream from hSAA2 exon 3 in the genome, which suggested that it is produced by alternative splicing. Furthermore, we succeeded in detecting and isolating hSAA3 protein for the first time by an immunoprecipitation-enzyme linked immune assay system using monoclonal and polyclonal antibodies that recognize the hSAA3 unique amino acid sequence. We also demonstrated that hSAA3 bound oxidized low density lipoprotein receptor (oxLDL receptor, LOX-1) and elevated the phosphorylation of ERK, the intracellular MAP-kinase signaling protein.

| S-EPMC4349446 | biostudies-literature

Oxidized low-density lipoprotein and peroxisome-proliferator-activated receptor alpha down-regulate platelet-activating-factor receptor expression in human macrophages.

Project description:Regulation of the expression of platelet-activating factor (PAF) receptor by atherogenic lipoproteins might contribute to atherogenesis. We show that progressive oxidation of low-density lipoprotein (LDL) gradually inhibits PAF receptor expression on the macrophage cell surface. We tested the effect of oxidized LDL (oxLDL) on PAF receptor expression in human monocytes that do not contain peroxisome-proliferator-activated receptor gamma (PPARgamma), a nuclear receptor activated by oxLDL. OxLDL decreased by 50% (P < or = 0.001) and by 29% (P < or = 0.05) the binding of PAF and the expression of PAF receptor mRNA respectively. Next we demonstrated that progressive oxidation of LDLs significantly activated PPARalpha-dependent transcription in transfected mouse aortic endothelial cells. Finally we demonstrated, in mature macrophages, that fenofibrate (20 microM), a specific PPARalpha agonist, but not the specific PPARgamma agonist BRL49653 (20 nM), significantly decreased both PAF binding and PAF receptor mRNA expression, by 65% and 40% (P < or = 0.001) respectively. Additionally, another PPARalpha agonist, Wy14,643, decreased PAF receptor promoter activity by 70% (P < or = 0.05) in transfected THP-1 cells, suggesting the involvement of the proximal promoter region (-980 to -500) containing a series of four nuclear factor (NF)-kappaB motifs. Thus PPARalpha might be involved in the down-regulation of PAF receptor gene expression by oxLDLs in human monocytes/macrophages. The oxidation of one or more lipid components of LDLs might result in the formation of natural activators of PPARalpha. It is hypothesized that such activators might modulate inflammation and apoptosis upon atherogenesis by decreasing the expression of PAF receptor.

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| S-EPMC9710765 | biostudies-literature

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Oxidized Low-Density Lipoprotein Promotes In Vitro Calcification.

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| 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

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

G0S2 ameliorates oxidized low-density lipoprotein-induced vascular endothelial cell injury by regulating mitochondrial apoptosis

Project description:Background Oxidative low-density lipoprotein (ox-LDL)-induced endothelial cell damage is a major risk factor for atherosclerosis and its related cardiovascular diseases. The G0/G1 switch gene 2 (G0S2) is a multifunctional protein which has been poorly studied in atherosclerosis. Methods In this study, ox-LDL was utilized to construct a human aortic endothelial cell (HAEC) injury model. Results It was found that ox-LDL impaired cell viability, augmented lactate dehydrogenase (LDH) release, and reduced G0S2 levels in HAECs in a dose-dependent manner. Further, G0S2 overexpression improved the viability and restrained apoptosis of HAECs treated by ox-LDL. Conversely, G0S2 depletion decreased the viability and aggravated apoptosis of HAECs treated by ox-LDL. At the molecular level, G0S2 overexpression significantly increased the secretion of superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPH-Px), promoted intracellular reactive oxygen species (ROS) production and malondialdehyde (MDA) content in HAECs under either normal or ox-LDL conditions. Meanwhile, the ox-LDL-induced mitochondrial dysfunction, as demonstrated by decreased mitochondrial membrane potential, translocation of mitochondrial cytochrome c (Cyt-c) to the cytoplasm, and activation of caspase-3 and caspase-9, was significantly reversed by G0S2 overexpression. In addition, G0S2 overexpression promoted the activation of AMP-activated protein kinase (AMPK) and increased the expression of nuclear factor erythroid-2-related factor-2 (Nrf2), sirtuin 1 (SIRT1) and heme oxygenase 1 (HO-1) under normal and ox-LDL conditions. Conclusions This study demonstrated that G0S2 protects against ox-LDL-induced vascular endothelial cell injury by regulating oxidative damage and mitochondrial homeostasis and may be a promising target for the treatment of atherosclerosis.

| S-EPMC9843419 | biostudies-literature

Oxidized Low-Density Lipoprotein Induces WNT5A Signaling Activation in THP-1 Derived Macrophages and a Human Aortic Vascular Smooth Muscle Cell Line.

Project description:The pathogenesis of atherosclerosis is complex, evolves, and involves many cell types. Macrophages and vascular smooth muscle cells (VSMCs) are critically involved in atherosclerosis development and progression. Several studies have shown that WNT5A protein is abundantly expressed in human atherosclerotic lesions; however, the mechanism and role of WNT signaling pathway activation is not clearly known. Using THP-1 derived macrophages, and human aortic VSMC cells, we evaluated in vitro how oxidized low-density lipoprotein (oxLDL) and WNT5A signaling interact in these two cell lines. We used western blot, scratch assay, metabolic proliferation assay, as well as immunostaining to analyze the effect of Wnt signaling activation. The results demonstrated that oxLDL, as well as WNT5A (control), induced Disheveled-2 (DVL2) activation and Kif26b degradation, indicating activation of non-canonical Wnt signaling. We found that oxLDL and WNT5A induced FZD5-ROR2 co-localization at the cellular membrane in vitro in THP-1 derived macrophages. Box5 (FZD5 receptor antagonist) inhibited oxLDL-induced DVL2/JNK activation secondary to newly secreted WNT protein from THP-1 derived macrophages. We found that WNT3A (canonical Wnt) and WNT5A showed different roles in this VSMC cell line. These findings indicate that WNT5A is upregulated by oxLDL, promotes foam cell formation, and affects VSMC phenotype and migration in these two cell lines. Also, in these cell lines FZD5 signaling seems to be necessary for lipid accumulation and, through this mechanism, WNT5A could modulate foam cell formation. Thus, our results suggest that WNT5A may contribute to the pathogenesis of vascular disease through modulating macrophage and VSMC behavior.

| S-EPMC7710548 | biostudies-literature

human primary monocytes: Control vs. oxLDL(oxidized low density lipoprotein)-stimulated 6h vs oxLDL-stimulated 12h

Project description:total RNA profiling of human primary monocytes comparing control untreated oxLDL cells with oxLDL cells for different time (6h and 12h), The latter makes monocytes to macrophage and foam cells.

2009-04-03 | GSE15514 | GEO

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