Increased oxidized low‐density lipoprotein in mice exposed to a high‐fat diet impaired spermatogenesis by inhibiting testosterone synthesis via the Klk1bs/Eid3 pathway
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ABSTRACT:
SUBMITTER: Yuan C
PROVIDER: S-EPMC10909978 | biostudies-literature | 2024 Mar
REPOSITORIES: biostudies-literature
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Project description:Neutrophil extracellular traps (NETs) are found in patients with various diseases, including cardiovascular diseases. We previously reported that copper-oxidized low-density lipoprotein (oxLDL) promotes NET formation of neutrophils, and that the resulting NETs increase the inflammatory responses of endothelial cells. In this study, we investigated the effects of high-density lipoproteins (HDL) on NET formation. HL-60-derived neutrophils were treated with phorbol 12-myristate 13-acetate (PMA) and further incubated with oxLDL and various concentrations of HDL for 2 h. NET formation was evaluated by quantifying extracellular DNA and myeloperoxidase. We found that the addition of native HDL partially decreased NET formation of neutrophils induced by oxLDL. This effect of HDL was lost when HDL was oxidized. We showed that oxidized phosphatidylcholines and lysophosphatidylcholine, which are generated in oxLDL, promoted NET formation of PMA-primed neutrophils, and NET formation by these products was completely blocked by native HDL. Furthermore, we found that an electronegative subfraction of LDL, LDL(-), which is separated from human plasma and is thought to be an in vivo oxLDL, was capable of promoting NET formation. These results suggest that plasma lipoproteins and their oxidative modifications play multiple roles in promoting NET formation, and that HDL acts as a suppressor of this response.
| S-EPMC9698465 | biostudies-literature
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
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
Project description:Cell therapy with bone marrow stem cells (BMSCs) remains a viable option for tissue repair and regeneration. A major challenge for cell therapy is the limited cell survival after implantation. This study was to investigate the effect of oxidized low-density lipoprotein (ox-LDL, naturally present in human blood) on BMSC injury and the effect of MG53, a tissue repair protein, for the improvement of stem cell survival. Rat bone marrow multipotent adult progenitor cells (MAPCs) were treated with ox-LDL, which caused significant cell death as reflected by the increased LDH release to the media. Exposure of MAPCs to ox-LDL led to entry of fluorescent dye FM1-43 measured under confocal microscope, suggesting damage to the plasma membrane. Ox-LDL also generated reactive oxygen species (ROS) as measured with electron paramagnetic resonance spectroscopy. While antioxidant N-acetylcysteine completely blocked ROS production from ox-LDL, it failed to prevent ox-LDL-induced cell death. When MAPCs were treated with the recombinant human MG53 protein (rhMG53) ox-LDL induced LDH release and FM1-43 dye entry were significantly reduced. In the presence of rhMG53, the MAPCs showed enhanced cell survival and proliferation. Our data suggest that membrane damage induced by ox-LDL contributed to the impaired survival of MAPCs. rhMG53 treatment protected MAPCs against membrane damage and enhanced their survival which might represent a novel means for improving efficacy for stem cell-based therapy for treatment of diseases, especially in setting of hyperlipidemia.
| S-EPMC4302650 | biostudies-literature
Project description:Atherosclerosis is characterized by retention of modified lipoproteins, especially oxidized low density lipoprotein (oxLDL) within the sub-endothelial space of affected blood vessels. Recruited monocyte-derived and tissue-resident macrophages subsequently ingest oxLDL by binding and internalizing oxLDL via scavenger receptors, particularly CD36. The secreted neurorepellent, Slit2, acting through its transmembrane receptor, Roundabout-1 (Robo-1), was previously shown to inhibit recruitment of monocytes into nascent atherosclerotic lesions. The effects of Slit2 on oxLDL uptake by macrophages have not been explored. We report here that Slit2 inhibits uptake of oxLDL by human and murine macrophages, and the resulting formation of foam cells, in a Rac1-dependent and CD36-dependent manner. Exposure of macrophages to Slit2 prevented binding of oxLDL to the surface of cells. Using super-resolution microscopy, we observed that exposure of macrophages to Slit2 induced profound cytoskeletal remodeling with formation of a thick ring of cortical actin within which clusters of CD36 could not aggregate, thereby attenuating binding of oxLDL to the surface of cells. By inhibiting recruitment of monocytes into early atherosclerotic lesions, and the subsequent binding and internalization of oxLDL by macrophages, Slit2 could represent a potent new tool to combat individual steps that collectively result in progression of atherosclerosis.
| S-EPMC7878733 | biostudies-literature
Project description:BACKGROUND:Macrophage accumulation in the vascular wall is a hallmark of atherosclerosis. Studies showed that shifting of oxidized lipids-induced inflammatory macrophages towards an anti-inflammatory phenotype by promoting oxidative metabolism attenuated atherosclerosis progression. Therefore, this study aimed to investigate whether metformin, which has ameliorated atherosclerosis in animal models and clinical trials, modulated oxidized low-density lipoprotein (Ox-LDL) induced inflammatory status in macrophages by regulating cellular oxidative metabolism. METHODS:Murine raw264.7 macrophages were incubated with Ox-LDL (50 μg/mL) in the presence or absence of metformin (15 μmol/L) for 24 h. Real-time polymerase chain reaction was used to quantify the transcription of classically activated (M1) pro-inflammatory and alternatively activated (M2) anti-inflammatory markers and mitochondrial DNA copy numbers. Cellular reactive oxygen species (ROS) production and mitochondrial membrane potential were detected by immunofluorescence. Cellular adenosine triphosphate (ATP) synthesis, glucose uptake, and lactic acid production were measured by commercial kit and normalized to cellular lysates. Western blotting analysis was performed to detect the expression of mitochondrial fusion/fission related proteins, enzymes mediating lipid metabolism and signaling pathway of glucose transport. Differences between groups were analyzed using one-way analysis of variance. RESULTS:Metformin improved Ox-LDL-impaired anti-inflammatory phenotype in raw264.7 macrophages as shown by up-regulated transcription of anti-inflammatory markers including interleukin 10 (0.76 ± 0.04 vs. 0.94 ± 0.01, P = 0.003) and Resistin-like molecule alpha (0.67 ± 0.08 vs. 1.78 ± 0.34, P = 0.030). Conversely, Ox-LDL-diminished phosphorylation of Akt was up-regulated by metformin treatment (0.47 ± 0.05 vs. 1.02 ± 0.08, P = 0.040), associated with an improvement of mitochondrial function, characterized by decreased ROS generation (2.50 ± 0.07 vs. 2.15 ± 0.04, P = 0.040), increased lipid oxidation, and elevated cellular ATP production (0.026 ± 0.001 vs. 0.035 ± 0.003, P = 0.020). Moreover, metformin-mediated Akt activation increased Akt substrate of 160 kDa (AS160) phosphorylation (0.51 ± 0.04 vs. 1.03 ± 0.03, P = 0.0041), promoted membrane translocation of glucose transporter 1, and increased glucose influx into the cells (4.78 ± 0.04 vs. 5.47 ± 0.01, P < 0.001). CONCLUSION:This study suggested that targeting macrophage metabolism with new or existing drugs had therapeutic potential for the prevention and treatment of diabetes-accelerated atherosclerosis.
| S-EPMC6759109 | biostudies-literature
Project description:Background Activated vascular cells produce submicron prothrombotic and proinflammatory microparticle vesicles. Atherosclerotic plaques contain high levels of microparticles. Plasma microparticle levels increase during acute coronary syndromes and the thrombotic consequences of plaque rupture likely involve macrophage-derived microparticles (MΦMPs). The activation pathways that promote MΦMP production remain poorly defined. This study tested the hypothesis that signals implicated in atherogenesis also stimulate MΦMP production. Methods and Results We stimulated human primary MΦs with proinflammatory cytokines and atherogenic lipids, and measured MΦMP production by flow cytometry. Oxidized low-density lipoprotein (oxLDL; 25 µg/mL) induced MΦMP production in a concentration-dependent manner (293% increase; P<0.001), and these oxLDL MΦMP stimulatory effects were mediated by CD36. OxLDL stimulation increased MΦMP tissue factor content by 78% (P<0.05), and oxLDL-induced MΦMP production correlated with activation of caspase 3/7 signaling pathways. Salvionolic acid B, a CD36 inhibitor and a CD36 inhibitor antibody reduced oxLDL-induced MΦMP by 67% and 60%, respectively. Caspase 3/7 inhibition reduced MΦMP release by 52% (P<0.01) and caspase 3/7 activation increased MΦMP production by 208% (P<0.01). Mevastatin pretreatment (10 µM) decreased oxLDL-induced caspase 3/7 activation and attenuated oxLDL-stimulated MΦMP production and tissue factor content by 60% (P<0.01) and 43% (P<0.05), respectively. Conclusions OxLDL induces the production of prothrombotic microparticles in macrophages. This process depends on caspases 3 and 7 and CD36 and is inhibited by mevastatin pretreatment. These findings link atherogenic signaling pathways, inflammation, and plaque thrombogenicity and identify a novel potential mechanism for antithrombotic effects of statins independent of LDL lowering.
| S-EPMC7792235 | biostudies-literature
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
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
Project description:Stress granules (SGs) in response to various stresses have been reported in many diseases. We previously reported the implication of programmed cell death 4 (Pdcd4) in obesity-induced stress responses, but the possible link between Pdcd4 and SGs remains lacking. In this study we showed that oxidized low-density lipoprotein (ox-LDL) or high-fat diet (HFD) induced SG formation in mouse macrophages and liver tissues, and Pdcd4 deficiency in mice remarkably reduced its formation. In response to ox-LDL, either endogenous or ectopic Pdcd4 displayed granule-like expression and co-localized with SG markers including T-cell-restricted intracellular antigen-1, fragile X mental retardation-related protein 1, and eukaryotic initiation factor 4A. Ectopic expression of truncated Pdcd4 that depleted specific RNA-binding motif significantly disrupted the SG formation, suggesting the direct involvement of Pdcd4 in ox-LDL-induced SGs through its RNA-binding activity. Additionally, Pdcd4 deficiency drove AKT activation and suppression of eIF2α phosphorylation, thereby contributing to the resistance to ox-LDL or HFD-induced SG formation. Collectively, our data suggest that Pdcd4 as a crucial regulator in SGs induced by ox-LDL or HFD maybe a potential target for mitigating SG-associated stress responses in obesity and related diseases.
| S-EPMC4959751 | biostudies-literature