Gene expression profile at single cell level of adipocyte tissue macrophages from Apoe-null eWAT
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE242120 | GEO | 2023/09/01
REPOSITORIES: GEO
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Project description:The multi-ligand Receptor for AGE (RAGE) contributes to atherosclerosis in apolipoprotein (ApoE) null mice in both the non-diabetic and diabetic states. Previous studies using soluble RAGE, the extracellular ligand-binding domain of RAGE, or homozygous RAGE null mice showed that blockade or deletion of RAGE resulted in marked reduction in atherosclerotic lesion area and complexity compared to control animals. In parallel, significant down-regulation of inflammatory mediators and matrix metalloproteinases was evident in ApoE null mice aortas devoid of RAGE compared to those of ApoE null RAGE-expressing mice. Although these findings suggested that RAGE triggered pro-atherogenic mechanisms via regulation of inflammatory gene expression, these studies did not reveal the broader pathways by which RAGE contributed to atherosclerosis in ApoE null mice. Therefore, we performed Affymetrix gene expression arrays on aortas of non-diabetic and diabetic ApoE null mice expressing RAGE or devoid of RAGE at nine weeks of age, as this reflected a time point at which frank atherosclerotic lesions were not yet present, but, that we would be able to identify the genes likely involved in diabetes- and RAGE-dependent atherogenesis. The comparisons were as follows: 1. diabetic ApoE null relative to non-diabetic ApoE null; 2. non-diabetic ApoE null / RAGE null relative to non-diabetic ApoE null; 3. diabetic ApoE null / RAGE null relative to non-diabetic ApoE null / RAGE null; and 4. diabetic ApoE null / RAGE null relative to diabetic ApoE null aorta. Our data reveal that there is very little overlap of the genes which are differentially expressed both in the onset of diabetes in ApoE null mice, and in the effect of RAGE deletion in diabetic ApoE null mice. We next performed a Pathway-Express analysis to determine the pathways that were most associated with the onset of diabetes in ApoE null mice and the effect of RAGE gene deletion in diabetic ApoE null mice. Rigorous statistical analysis was undertaken and revealed that the transforming growth factor-beta pathway (tgf-beta) and focal adhesion pathways might be expected to play a significant role in both the mechanism by which diabetes facilitates the formation of atherosclerotic plaques in ApoE null mice, and the mechanism by which deletion of RAGE ameliorates this effect. We focused on three genes of the tgf-betafamily which were found to be up-regulated in diabetic vs. non-diabetic ApoE null aorta, and which were reduced by deletion of RAGE. These included: thrombospondin1 (Thbs1), transforming growth factor-beta (tgf-beta) and rho-associated kinase (ROCK1). Real-time quantitative polymerase chain reaction and Western blotting experiments were performed, as well as ROCK1 activity assays in mouse aorta, and validated the findings of the Affymetrix gene array. Further, confocal microscopy revealed that a principal cell type in the ApoE null aorta expressing these factors was the vascular smooth muscle cell. Our data suggest the novel finding that the observed reduction of accelerated atherosclerosis in diabetic ApoE null / RAGE null vs. diabetic ApoE null mice occurs, all or in part, through the ROCK1 branch of the TGF-betapathway. We have inferred a detailed mechanism for this process. Taken together, these data suggest that suppression of ROCK1 activity in the atherosclerosis-vulnerable vessel wall, especially in diabetes, but in non-diabetes as well, may underlie the beneficial effects of RAGE antagonism and genetic deletion in murine models. These findings highlight logical and novel targets for therapeutic intervention in cardiovascular disease and diabetes. 1. diabetic ApoE null relative to non-diabetic ApoE null; 2. non-diabetic ApoE null / RAGE null relative to non-diabetic ApoE null; 3. diabetic ApoE null / RAGE null relative to non-diabetic ApoE null / RAGE null; and 4. diabetic ApoE null / RAGE null relative to diabetic ApoE null aorta. There were 4 mice in each group initially. However there are only 3 non-diabetic ApoE null / RAGE null mice in the final experimental sample in group 3 due to a failure to generate cRNA from that sample. All samples were normalized to remove chip-dependent regularities using the RMA method. Chips and controls at each combination of genotype and disease sate were normalized together. The statistical significance of differential expression was calculated using the empirical Bayesian LIMMA (LInear Model for MicroArrays) method A cut-off B>0 was used for the statistical significance of gene expression.
2010-03-07 | E-GEOD-15729 | biostudies-arrayexpress
Project description:The multi-ligand Receptor for AGE (RAGE) contributes to atherosclerosis in apolipoprotein (ApoE) null mice in both the non-diabetic and diabetic states. Previous studies using soluble RAGE, the extracellular ligand-binding domain of RAGE, or homozygous RAGE null mice showed that blockade or deletion of RAGE resulted in marked reduction in atherosclerotic lesion area and complexity compared to control animals. In parallel, significant down-regulation of inflammatory mediators and matrix metalloproteinases was evident in ApoE null mice aortas devoid of RAGE compared to those of ApoE null RAGE-expressing mice. Although these findings suggested that RAGE triggered pro-atherogenic mechanisms via regulation of inflammatory gene expression, these studies did not reveal the broader pathways by which RAGE contributed to atherosclerosis in ApoE null mice. Therefore, we performed Affymetrix gene expression arrays on aortas of non-diabetic and diabetic ApoE null mice expressing RAGE or devoid of RAGE at nine weeks of age, as this reflected a time point at which frank atherosclerotic lesions were not yet present, but, that we would be able to identify the genes likely involved in diabetes- and RAGE-dependent atherogenesis. The comparisons were as follows: 1. diabetic ApoE null relative to non-diabetic ApoE null; 2. non-diabetic ApoE null / RAGE null relative to non-diabetic ApoE null; 3. diabetic ApoE null / RAGE null relative to non-diabetic ApoE null / RAGE null; and 4. diabetic ApoE null / RAGE null relative to diabetic ApoE null aorta. Our data reveal that there is very little overlap of the genes which are differentially expressed both in the onset of diabetes in ApoE null mice, and in the effect of RAGE deletion in diabetic ApoE null mice. We next performed a Pathway-Express analysis to determine the pathways that were most associated with the onset of diabetes in ApoE null mice and the effect of RAGE gene deletion in diabetic ApoE null mice. Rigorous statistical analysis was undertaken and revealed that the transforming growth factor-β pathway (tgf-β) and focal adhesion pathways might be expected to play a significant role in both the mechanism by which diabetes facilitates the formation of atherosclerotic plaques in ApoE null mice, and the mechanism by which deletion of RAGE ameliorates this effect. We focused on three genes of the tgf-β family which were found to be up-regulated in diabetic vs. non-diabetic ApoE null aorta, and which were reduced by deletion of RAGE. These included: thrombospondin1 (Thbs1), transforming growth factor-β2 (tgf-β2) and rho-associated kinase (ROCK1). Real-time quantitative polymerase chain reaction and Western blotting experiments were performed, as well as ROCK1 activity assays in mouse aorta, and validated the findings of the Affymetrix gene array. Further, confocal microscopy revealed that a principal cell type in the ApoE null aorta expressing these factors was the vascular smooth muscle cell. Our data suggest the novel finding that the observed reduction of accelerated atherosclerosis in diabetic ApoE null / RAGE null vs. diabetic ApoE null mice occurs, all or in part, through the ROCK1 branch of the TGF-β pathway. We have inferred a detailed mechanism for this process. Taken together, these data suggest that suppression of ROCK1 activity in the atherosclerosis-vulnerable vessel wall, especially in diabetes, but in non-diabetes as well, may underlie the beneficial effects of RAGE antagonism and genetic deletion in murine models. These findings highlight logical and novel targets for therapeutic intervention in cardiovascular disease and diabetes.
2010-03-01 | GSE15729 | GEO
Project description:Gene expression profile at single cell level of adipocyte tissue macrophages from Apoe-null eWAT
| PRJNA1011392 | ENA
Project description:Hypercholesterolemic APOE-deficient mice are a widely used experimental model of atherosclerosis and increased generation of reactive oxygen species (ROS) is a prominent feature of atherosclerosis development. To study the impact of ROS on atherogenesis, we treated APOE-deficient mice for 7 months with the antioxidant vitamin E (2000 IU/kg diet) and performed whole genome microarray gene expression profiling of aortic genes. Microarray gene expression profiling was performed of whole aortas isolated from vitamin E-treated APOE-deficient relative to untreated APOE-deficient mice with overt atherosclerosis, and nontransgenic B6 control mice. Microarray gene expression profiling revealed that vitamin E treatment prevented atherosclerosis-related gene expression changes of the aortic intima and media. Microarray gene expression profiling was performed of whole aortas isolated from APOE-deficient mice with atherosclerosis relative to vitamin E-treated APOE-deficient mice, and nontransgenic B6 control mice. Three study groups were analyzed, i.e. 8 months-old untreated APOE-deficient mice with overt atherosclerosis, age-matched APOE-deficient mice treated for 7 months with the antioxidant vitamin E (2000 IU/kd diet), and nontransgenic B6 control (C57BL/6J) mice. Two biological replicates were made of each group, and total RNA of three aortas was pooled for one gene chip. The study complements microarray study GSE19286.
2012-12-11 | E-GEOD-42813 | biostudies-arrayexpress
Project description:Hypercholesterolemic APOE-deficient mice are a widely used experimental model of atherosclerosis and increased generation of reactive oxygen species (ROS) is a prominent feature of atherosclerosis development. To study the impact of ROS on atherogenesis, we treated APOE-deficient mice for 7 months with the antioxidant vitamin E (2000 IU/kg diet) and performed whole genome microarray gene expression profiling of aortic genes. Microarray gene expression profiling was performed of whole aortas isolated from vitamin E-treated APOE-deficient relative to untreated APOE-deficient mice with overt atherosclerosis, and nontransgenic B6 control mice. Microarray gene expression profiling revealed that vitamin E treatment prevented atherosclerosis-related gene expression changes of the aortic intima and media.
2012-12-11 | GSE42813 | GEO
Project description:Hypertriglyceridemia results from accumulation of triglyceride (TG)-rich lipoproteins (TRLs) in the circulation and is associated with increased cardiovascular disease risk. ApoC-III is an apolipoprotein on TRLs and a prominent negative regulator of TG catabolism. We recently established that in vivo apoC-III predominantly inhibits LDLR and LRP1 mediated hepatic TRL clearance and that apoC-III enriched TRLs are preferentially cleared by syndecan-1 (SDC1). In this study, we determined the impact of apoE, a common ligand for all three receptors, on apoC-III metabolism using apoC-III antisense oligonucleotide (ASO) treatment in mice lacking apoE and functional SDC1 (Apoe(-/-) Ndst1(f/f) Alb-Cre+). ApoC-III ASO treatment significantly reduced plasma TG levels in Apoe(-/-) Ndst1(f/f) Alb-Cre+ mice without reducing hepatic VLDL production or improving hepatic TRL clearance. Further analysis revealed that apoC-III ASO treatment lowered plasma TGs in Apoe(-/-) Ndst1(f/f) Alb-Cre+ mice, which was associated with increased LPL activity in white adipose tissue (WAT) in the fed state. Finally, clinical data confirm that ASO-mediated lowering of apoC-III via volanesorsen can reduce plasma TG levels independent of the apoE isoform genotype. Our data indicate that apoE determines the metabolic impact of apoC-III as we establish that apoE is essential to mediate inhibition of TRL clearance by apoC-III and that in the absence of functional apoE apoC-III inhibits tissue LPL activity.
2019-05-24 | GSE131284 | GEO
Project description:Circulating microRNAs (miRNA) are relatively stable in plasma and are a new class of disease biomarkers. Here we present evidence that human high-density lipoprotein (HDL) transports endogenous miRNAs and delivers them to recipient cells with functional targeting capabilities. Highly-purified fractions of human HDL contain small RNAs, and the HDL-miRNA profile from normal subjects is significantly different than familial hypercholesterolemia subjects. miRNAs were demonstrated to associate with both native and reconstituted HDL particles, and reconstituted HDL injected into mice retrieved distinct miRNA profiles from normal and atherogenic models. Cellular export of miRNAs to HDL was demonstrated to be regulated by neutral sphingomyelinase. HDL-mediated delivery of miRNAs to recipient cells was demonstrated to be scavenger receptor BI-dependent. Furthermore, HDL delivery of both exogenous and endogenous miRNAs resulted in the direct targeting of mRNA reporters. Notably, HDL-miRNA from atherosclerotic subjects induced differential gene expression, with significant loss of conserved mRNA targets in cultured hepatocytes. Collectively, these observations suggest that HDL participates in a novel mechanism of intercellular communication involving the transport and delivery of miRNAs. microRNA signatures retrieved from rHDL injected into WT, ApoE-/- chow, ApoE-/-high fat diet Profiled rHDL miRNA signatures from n=3 WT; n=3 ApoE-/- chow, n=4 ApoE-/- high fat mice
2011-03-23 | E-GEOD-25424 | biostudies-arrayexpress
Project description:The role of TIMP3 in the context of cardiovascular remodeling is relatively unexplored when considering classical risk factors such as hypercholesterolemia, diabetes and hypertension. To learn more the role of TIMP3 in the progression of cardiovascular disease we combined genetics, metabolomics and in vivo phenotypical analysis using the hypercholesterolemic ApoE null mice to generate ApoE-/-Timp3-/- mice, the latter showing increased atherosclerosis, increased mortality and arrhythmias compared to ApoE-/- mice. We have previously described Timp3-/-mice in ( Fiorentino, L., et al., Regulation of TIMP3 in diabetic nephropathy: a role for microRNAs. Acta Diabetol, 2013) . To generate ApoE-/-Timp3-/- knockout animals we crossbred the 2 strains. Offsprings were then backcrossed into ApoE animals for 6 generations to generate a pure lineage. Collectively, metabolite profiles, gene and protein expression consistently suggested a role for TIMP3 to underlie a decreased activation of PPARα/AMPK to dampen fatty acids β-oxidation eventually leading to atherosclerotic plaque composition vulnerability and perturbation of heart metabolism. mRNA profiling in ApoE-/-Timp3-/- mice revealed a TIMP3 effect to regulate Apelin, which we found decreased in the circulation due to its specific downregulation at the myocardial level but not in other well known sites of expression such as the adipose tissue. mRNA sequencing of the heart of ApoE-/-Timp3-/- mice vs ApoE-/- littermates controls.
2015-01-01 | E-GEOD-53548 | biostudies-arrayexpress
Project description:VSMC-specific MT1-MMP gene targeting in APOE-null mice promotes atherosclerosis and iliac artery aneurysm formation. To determine the MT1-MMP-dependent regulation of VSMC function, whole-genome transcriptomes of wild-type and MT1-MMP-null APOE-null VSMCs were determined. We used microarray-based transcriptome analysis to detect MT1-MMP-dependent regulation of VSMC function under atherogenic conditions.
2017-08-01 | GSE100661 | GEO
Project description:Enhancers, critical regulatory elements within the human genome, are often transcribed into enhancer RNAs. The dysregulation of enhancers leads to diseases collectively termed enhanceropathies. While it is known that enhancers play a role in diseases by regulating gene expression, the specific mechanisms by which individual enhancers cause diseases are not well understood. Studies of individual enhancers are needed to fill this gap. This study delves into the role of APOE-activating noncoding RNA, AANCR, in the central nervous system, elucidating its function as a genetic modifier in Alzheimer's Disease. We employed RNA interference, RNaseH-mediated degradation, and single-molecule RNA fluorescence in situ hybridization to demonstrate that mere transcription of AANCR is insufficient; rather, its transcripts are crucial for promoting APOE expression. Our findings revealed that AANCR is induced by ATM-mediated ERK phosphorylation and subsequent AP-1 transcription factor activation. Once activated, AANCR enhances APOE expression, which in turn imparts an inflammatory phenotype to astrocytes. These findings demonstrate that AANCR is a key enhancer RNA in some cell types within the nervous system, pivotal for regulating APOE expression and influencing inflammatory responses, underscoring its potential as a therapeutic target in neurodegenerative diseases.
2024-08-22 | GSE263862 | GEO