Changes in macrophages and endothelial cells mechanics treated with native LDL from donors with CVD
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PROVIDER: PRJNA1295491 | ENA |
REPOSITORIES: ENA
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Project description:Atherosclerosis is a progressive and multifactorial vascular disorder characterized by lipid accumulation, chronic inflammation, and structural alterations in the arterial wall. This condition disrupts normal endothelial function, including the biomechanical properties of endothelial cells, which play a crucial role in maintaining vascular homeostasis. Mechanical dysfunction in these cells contributes to increased vascular permeability and topographical irregularities that disturb hemodynamic flow, fostering an environment conducive to plaque development. A growing body of evidence suggests that low-density lipoprotein (LDL) exacerbates these dysfunctions by increasing cellular stiffness. As endothelial cells act as primary mechanosensors within blood vessels, their altered mechanical state is a critical factor in early atherogenesis. In this study, we explored the molecular pathways by which native LDL, derived from individuals with cardiovascular disease, affects the mechanical and structural properties of endothelial cells and macrophages. Our analyses revealed that exposure to native LDL triggers a pronounced reorganization of the actin cytoskeleton, primarily mediated through Rho GTPase signaling, along with notable augmentation of the tubulin network. These cytoskeletal changes were accompanied by compromised cell adhesion, weakened intercellular connectivity, and impaired extracellular matrix integrity—all of which are pivotal to endothelial barrier function. Furthermore, gene expression profiling indicated a significant upregulation of LOX, HMOX1, RND1, RUNX1, and TFRC in LDL-treated endothelial cells, suggesting a disruption in iron metabolism. This dysregulation likely contributes to oxidative stress through reactive oxygen species (ROS) production, thereby accelerating atherosclerotic plaque formation.
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2016-02-09 | GSE68021 | GEO
Project description:Early transcriptomic response to n-LDL and ox-LDL in human vascular smooth muscle cells (hVSMC). We used microarrays with the aim of assessing early molecular changes that induce a response in the VSMC using native and oxidized low-density lipoprotein (n-LDL and ox-LDL). For each LDL internalization experiment, three biological replicates were used and the samples pooled with the aim of obtain three technical replicates (three arrays for condition).
2016-02-09 | E-GEOD-68021 | biostudies-arrayexpress
Project description:The method of digitized native protein mapping, combining nondenaturing micro 2DE, grid gel-cutting and quantitative LC-MS/MS (in data-independent acquisition mode, or MSE), was improved by using a new MS/MS mode, ion mobility separation enhanced-MSE (HDMSE) and applied to analyze the area of human plasma low-density lipoproteins (LDL). An 18 mm * 4.8 mm rectangular area which included LDL on a nondenaturing micro 2D gel of human plasma was grid-cut into 72 square gel pieces and subjected to quantitative LC-MS/MS. Compared with MSE, HDMSE showed significantly higher performance, by assigning 50% more proteins and detecting each protein in more squares. Totally 253 proteins were assigned with LC-HDMSE and the quantity distribution of each was reconstructed as a native protein map. The maps showed Apo B-100 was the most abundant protein in the grid-cut area, concentrated at pI 5.4-6.1 and apparent mass ca. 1000 kDa, which corresponded to four gel pieces, squares 39-42. An Excel macro was prepared to search protein maps which show protein quantity peaks localized within the concentrated region of Apo B-100 (squares 39-42). Twenty-two proteins out of the 252 matched this criteria, in which nineteen proteins have been reported to be associated with LDL. This method require only several microliters of a plasma sample and the principle of the protein separation is totally different from ultracentrifugation. The results obtained by this method would provide new insights on the structure and function of LDL.
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Project description:We conducted a global transcriptional profiling using microarray analysis of the response of EC exposed either to native LDL or LDL-X
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Project description:We previously found that a native lipoprotein mix with a high VLDL+LDL/HDL ratio causes a global de novoDNA methylation in THP-1 macrophages. In the present experiment we assessed the consequences of global lipoprotein-induced de novo DNA methylation on global gene expression in the same cells. Moreover, we sought to use gene expression array data to measure RNA expression levels for candidate factors mediating the epigenetic effects of lipoproteins. Experiment Overall Design: Human native VLDL, LDL and HDL lipoproteins were isolated from buffy coats, fractionated by ultracentrifugation, stored at -80deg., desalted to PBS before usage and kept at 4deg. for a maximum of 7d. THP-1 monocytes were differentiated to macrophages, stimulated for 24h with a mix of 68.8mg/ml VLDL, 32.1mg/ml LDL, 91.1mg/ml HDL or unstimulated (control), in serum-free medium with 2% BSA. Three independently isolated lipoprotein samples were used in triplicate.
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Project description:Electronegative LDL (LDL(-)) is a minor modified fraction of human plasma LDL with several atherogenic properties. Among them, LDL(-) has increased content of bioactive lipid mediators, such as lysophosphatidylcholine (LPC), non-esterified fatty acids (NEFA), ceramide (Cer), and sphingosine (Sph), which are related to the presence in LDL(-) of some phospholipolytic activities, including platelet-activating factor acetylhydrolase (PAF-AH), phospholipase C (PLC) and sphingomyelinase (SMase). However, the activity of these enzymes does not explain the increased content of Sph, which should derive from Cer degradation. In the present study we analyzed the putative presence of a ceramidase (CDase) activity that could explain the increased content of Sph. Thin layer chromatography (TLC) and lipidomic analysis showed that Cer, Sph and NEFA spon-taneously increased in LDL(-) incubated alone at 37ºC, in contrast with native LDL(+). An inhibitor of neutral CDase prevented the formation of Sph and, in contrast, increased the content of Cer in LDL(-). In addition, a fluorescently-labelled Cer (NBD-Cer) was efficiently degraded by LDL(-) to form Sph and NEFA. These observations point to the existence of a CDase activity associated to LDL(-). However, neither proteomic analysis nor western blot detected the presence of a known CDase enzyme. Further studies are warranted to define the origin of the CDase activity detected in LDL(-).
2023-01-09 | PXD036168 | Pride
Project description:LDL or Ox-LDL 200ug/ml, which showed no loss of viability after a 48 hour exposure, induced a physiological and pathological transcriptional response, respectively. LDL induced a downregulation of genes associated with cholesterol biosynthesis while ox-LDL induced transcriptional alterations in genes related to inflammation, matrix expansion, lipid metabolism and processing, and apoptosis. Pentraxin-3 was secreted into the culture medium after RPE cells were stimulated with ox-LDL, and immunohistochemically evident in Bruchs membrane of human macular samples with age-related macular degeneration. ARPE-19 cells exposed to 200ug/ml ox-LDL had a 38% apoptosis rate compared to less than 1% when exposed to LDL or untreated controls (p<0.0001). While LDL induced a physiologic response by RPE cells, a pathological phenotypic response was seen after treatment with oxidatively modified LDL. The transcriptional, biochemical, and functional data provide initial support of a role for the hypothesis that modified LDLs are one trigger for initiating events that contribute to the development of age-related macular degeneration. Keywords: treatment with non-treatment control Human ARPE-19 cells were exposed to LDL or oxidatively modified LDL (ox-LDL) for 48 hours for RNA extraction and hybridization on Affymetrix microarrays. We sought to determine whether retina, pigment epithelial cells develop a pathologic phenotype after exposure to low density lipoproteins (LDL) that are oxidatively modified.We have made two comparsions: LDL treatment versus non-treatment; ox-LDL treatment versus non-treatment.
2006-09-01 | E-GEOD-5741 | biostudies-arrayexpress
Project description:LDL or Ox-LDL 200ug/ml, which showed no loss of viability after a 48 hour exposure, induced a physiological and pathological transcriptional response, respectively. LDL induced a downregulation of genes associated with cholesterol biosynthesis while ox-LDL induced transcriptional alterations in genes related to inflammation, matrix expansion, lipid metabolism and processing, and apoptosis. Pentraxin-3 was secreted into the culture medium after RPE cells were stimulated with ox-LDL, and immunohistochemically evident in Bruch’s membrane of human macular samples with age-related macular degeneration. ARPE-19 cells exposed to 200?g/ml ox-LDL had a 38% apoptosis rate compared to less than 1% when exposed to LDL or untreated controls (p<0.0001). While LDL induced a physiologic response by RPE cells, a pathological phenotypic response was seen after treatment with oxidatively modified LDL. The transcriptional, biochemical, and functional data provide initial support of a role for the hypothesis that modified LDLs are one trigger for initiating events that contribute to the development of age-related macular degeneration. Keywords: treatment with non-treatment control
2006-09-01 | GSE5741 | GEO
Project description:Hippo effectors YAP/TAZ act as on-off mechanosensing switches by sensing modifications in extracellular matrix (ECM) composition and mechanics. The regulation of their activity has been described so far through a hierarchical model in which elements of Hippo pathway are under the control of Focal Adhesions (FAs). Here we unveiled the molecular mechanism by which cell spreading and RhoA GTPase control FA formation through YAP to stabilize the anchorage of actin cytoskeleton to cell membrane. This mechanism required YAP co-transcriptional function and involved the activation of genes encoding for integrins and FA docking proteins. Tuning YAP transcriptional activity led to the modification of cell mechanics, force development, adhesion strength, determined cell shaping, migration and differentiation. These results provide new insights into the mechanism of YAP mechanosensing activity and qualify Hippo effector as the key determinant of cell mechanics in response to ECM cues.
2017-05-17 | E-MTAB-5217 | biostudies-arrayexpress