Circulating miRNA profile and coronary calcification in asymptomatic patients with familial hypercholesterolemia.
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ABSTRACT:
ORGANISM(S): synthetic construct Homo sapiens
PROVIDER: GSE178126 | GEO | 2024/03/26
REPOSITORIES: GEO
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Project description:Atherosclerosis is the major cause of death in industrialized countries. This disease has initially been characterized as a lipid disorder, but current concepts argue for an inflammatory disease, which develops in the background of hypercholesterolemia and other risk factors. In response to initial events of atherosclerosis formation, such as LDL-deposition in the subendothelial space, monocytes and T cells interact with the vessel wall. However, little is known about the properties and the behavior of these cells in this context. Using familial hypercholesterolemia (FH) as a model we demonstrate substantial differences in the gene expression of freshly isolated human monocytes and T lymphocytes. In FH monocytes we found an increased uptake of oxidized LDL, elevated amounts of scavenger receptors and adhesion molecules, and differences in the regulation of intracellular lipoprotein metabolism compared to monocytes from healthy individuals. Furthermore, the monocyte subpopulation of CD14+/CD16+ cells is less frequent in FH but exhibits significantly higher levels of CD11c and CD29 which increases the likelihood for their transmigration through the endothelial layer. The presence of increased amounts of CD69 in T lymphocytes from FH patients suggests that these cells are more activated than control cells. Our results indicate that some important steps of atherosclerosis formation already take place in circulating blood cells which extends current atherosclerosis models to the plasma compartment. Experiment Overall Design: 25 monocytes samples: 5 homozygous FH, 7 heterozygous FH, 13 control participants
2008-06-14 | E-GEOD-6054 | biostudies-arrayexpress
Project description:Atherosclerosis is the major cause of death in industrialized countries. This disease has initially been characterized as a lipid disorder, but current concepts argue for an inflammatory disease, which develops in the background of hypercholesterolemia and other risk factors. In response to initial events of atherosclerosis formation, such as LDL-deposition in the subendothelial space, monocytes and T cells interact with the vessel wall. However, little is known about the properties and the behavior of these cells in this context. Using familial hypercholesterolemia (FH) as a model we demonstrate substantial differences in the gene expression of freshly isolated human monocytes and T lymphocytes. In FH monocytes we found an increased uptake of oxidized LDL, elevated amounts of scavenger receptors and adhesion molecules, and differences in the regulation of intracellular lipoprotein metabolism compared to monocytes from healthy individuals. Furthermore, the monocyte subpopulation of CD14+/CD16+ cells is less frequent in FH but exhibits significantly higher levels of CD11c and CD29 which increases the likelihood for their transmigration through the endothelial layer. The presence of increased amounts of CD69 in T lymphocytes from FH patients suggests that these cells are more activated than control cells. Our results indicate that some important steps of atherosclerosis formation already take place in circulating blood cells which extends current atherosclerosis models to the plasma compartment. Experiment Overall Design: 23 T cells samples: 3 homozygous FH, 7 heterozygous FH, 13 control participants
2008-06-14 | E-GEOD-6088 | biostudies-arrayexpress
Project description:Atherosclerosis is the major cause of death in industrialized countries. This disease has initially been characterized as a lipid disorder, but current concepts argue for an inflammatory disease, which develops in the background of hypercholesterolemia and other risk factors. In response to initial events of atherosclerosis formation, such as LDL-deposition in the subendothelial space, monocytes and T cells interact with the vessel wall. However, little is known about the properties and the behavior of these cells in this context. Using familial hypercholesterolemia (FH) as a model we demonstrate substantial differences in the gene expression of freshly isolated human monocytes and T lymphocytes. In FH monocytes we found an increased uptake of oxidized LDL, elevated amounts of scavenger receptors and adhesion molecules, and differences in the regulation of intracellular lipoprotein metabolism compared to monocytes from healthy individuals. Furthermore, the monocyte subpopulation of CD14+/CD16+ cells is less frequent in FH but exhibits significantly higher levels of CD11c and CD29 which increases the likelihood for their transmigration through the endothelial layer. The presence of increased amounts of CD69 in T lymphocytes from FH patients suggests that these cells are more activated than control cells. Our results indicate that some important steps of atherosclerosis formation already take place in circulating blood cells which extends current atherosclerosis models to the plasma compartment. Keywords: atherosclerosis, T cells, Familial Hypercholesterolemia
2008-04-01 | GSE6088 | GEO
Project description:Background: Elevated plasma cholesterol promotes the formation of atherosclerotic lesions in which monocyte-derived lipid-laden macrophages are frequently found. To analyze, if circulating monocytes already show increased lipid content and differences in lipoprotein metabolism, we compared monocytes from patients with Familial Hypercholesterolemia (FH) with those from healthy individuals. Methods: Cholesterol and oxidized cholesterol metabolite serum levels of FH and of healthy, gender/age matched control subjects were measured by combined gas chromatography ? mass spectroscopy. Monocytes from patients with FH and from healthy subjects were isolated by antibody-assisted density centrifugation. Gene expression profiles of isolated monocytes were measured using Affymetrix HG-U 133 Plus 2.0 microarrays. We compared monocyte gene expression profiles from FH patients with healthy controls using a Welch T-test with correction for multiple testing (p < 0.05; Benjamini Hochberg correction, False Discovery Rate = 0.05). The differential expression of FH associated genes was validated at the mRNA level by qRT-PCR and/or at the protein level by Western Blot or flow cytometry. Functional validation of monocyte scavenger receptor activities were done by binding assays and dose/time dependent uptake analysis using native and oxidized LDL. Results: Using microarray analysis we found in FH patients a significant up-regulation of 1,617 genes and a down-regulation of 701 genes compared to monocytes from healthy individuals. These include genes of proteins that are involved in the uptake, biosynthesis, disposition, and cellular efflux of cholesterol. In addition, plasma from FH patients contains elevated amounts of sterols and oxysterols. An increased uptake of oxidized as well as of native LDL by FH monocytes combined with a down-regulation of NPC1 and ABCA1 explains the lipid accumulation observed in these cells. Conclusion: Our data demonstrate that circulating FH monocytes show differences in cell physiology that may contribute to the early onset of atherosclerosis in this disease. Keywords: Micro-array analysis, cell type comparison,
2008-04-01 | GSE6054 | GEO
Project description:To investigate effects of IGF-1 on human-like coronary atherosclerosis we used high fat diet-fed Rapacz pigs with familial hypercholesterolemia (FH pigs). We used spatial transcriptomics (ST) analysis to identify global transcriptome changes in advanced plaque compartments and to obtain mechanistic insights into IGF-1 effects. IGF-1-injected FH pigs had 1.8-fold increase in total circulating IGF-1 levels compared to control. IGF-1 decreased relative coronary atheroma (data obtained by serial intravascular ultrasound) and lesion cross-sectional area (post-mortem histology). IGF-1 increased fibrous cap thickness, and reduced necrotic core size, macrophage content, and cell apoptosis, changes consistent with promotion of a stable plaque phenotype. ST analysis revealed that IGF-1 suppressed FOS/FOSB factors and gene expression of MMP9 and CXCL14 suggesting possible involvement of these molecules in IGF-1’s effect on atherosclerosis.
2023-12-03 | GSE220218 | GEO
Project description:Clino Molecular study of FH disease - to identify the variations that result in FH disorder. <br><br>If you are looking for the data for publication "Molecular Characterization of Breast Cancer with High-Resolution Oligonucleotide Comparative Genomic Hybridization Array" please search for accession E-TABM-484 (the accession number was quoted incorrectly in the paper)
2009-04-07 | E-TABM-584 | biostudies-arrayexpress
Project description:Total RNA pools from macrophages from Familial Hypercholesterolemia(FH) patients with tendon xanthomas (TX+) and without tendon xanthomas (TX-) were analyzed using Affymetrix oligonucleotide arrays (HGU133A) to evaluate the gene expression profile in presence and absence of oxidized LDL.
2006-01-01 | E-MEXP-360 | biostudies-arrayexpress
Project description:In familial hypercholesterolemia (FH), mutations in the low-density lipoprotein (LDL) receptor (LDLr) gene result in increased plasma LDL cholesterol. Clinical and preclinical studies revealed an association between FH and hippocampus-related memory and mood impairment. We here asked whether hippocampal pathology in FH might be a consequence of compromised adult hippocampal neurogenesis. We evaluated hippocampus-dependent behaviour and neurogenesis in adult C57BL/6JRj and LDLr-/- mice. Behavioural tests revealed that adult LDLr-/- mice showed reduced performance in a dentate gyrus (DG)-dependent metric change task. This phenotype was accompanied by a reduction in cell proliferation and adult neurogenesis in the DG of LDLr-/- mice, suggesting a potential direct impact of LDLr mutation on NPC. We thus investigated the effects of elevated cholesterol and the function of LDLr in neural precursor cells (NPC) isolated from adult C57BL/6JRj mice in vitro. Exposure of NPC to LDL as well as LDLr gene knockdown reduced proliferation and disrupted transcriptional activity of genes involved in endogenous cholesterol synthesis and metabolism. The LDL treatment also induced an increase in intracellular lipid storage. Functional analysis of differentially expressed genes revealed parallel modulation of distinct regulatory networks upon LDL treatment and LDLr knockdown. Together, these results suggest that high LDL levels and a loss of LDLr function, which are characteristic to individuals with FH, might contribute to a disease-related impairment in adult hippocampal neurogenesis and, consequently, cognitive functions.
2019-09-04 | GSE136792 | GEO
Project description:In familial hypercholesterolemia (FH), mutations in the low-density lipoprotein (LDL) receptor (LDLr) gene result in increased plasma LDL cholesterol. Clinical and preclinical studies revealed an association between FH and hippocampus-related memory and mood impairment. We here asked whether hippocampal pathology in FH might be a consequence of compromised adult hippocampal neurogenesis. We evaluated hippocampus-dependent behaviour and neurogenesis in adult C57BL/6JRj and LDLr-/- mice. Behavioural tests revealed that adult LDLr-/- mice showed reduced performance in a dentate gyrus (DG)-dependent metric change task. This phenotype was accompanied by a reduction in cell proliferation and adult neurogenesis in the DG of LDLr-/- mice, suggesting a potential direct impact of LDLr mutation on NPC. We thus investigated the effects of elevated cholesterol and the function of LDLr in neural precursor cells (NPC) isolated from adult C57BL/6JRj mice in vitro. Exposure of NPC to LDL as well as LDLr gene knockdown reduced proliferation and disrupted transcriptional activity of genes involved in endogenous cholesterol synthesis and metabolism. The LDL treatment also induced an increase in intracellular lipid storage. Functional analysis of differentially expressed genes revealed parallel modulation of distinct regulatory networks upon LDL treatment and LDLr knockdown. Together, these results suggest that high LDL levels and a loss of LDLr function, which are characteristic to individuals with FH, might contribute to a disease-related impairment in adult hippocampal neurogenesis and, consequently, cognitive functions.
2019-09-04 | GSE136797 | GEO
Project description:Atherosclerosis is a chronic disease involving multiple biological mechanisms. A study aimed to identify changes in miRNA expression at early stages using a large swine model. 18 female pigs were studied, 9 with familial hypercholesterolemia and 9 normal controls. Plasma was collected at 3, 6, and 9 months of age. In vivo imaging and histopathology were performed to document the presence of coronary atherosclerosis. miRNA sequencing was carried out on plasma cell-free RNA. Results showed that circulating miRNA dynamics change over time during atherosclerosis development and specific DE miRNAs may be promising biomarkers for early detection of coronary atherosclerosis.
2023-11-08 | GSE242074 | GEO