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Attenuation of early atherogenesis in LDLR-KO mice by proteasome inhibition

ABSTRACT: To get further insights into the processes leading to attenuation of early stage atherosclerosis in the bortezomib treated LDLR-KO mice, microarray profiling of gene expression was performed on RNA taken from whole aortae of bortezomib treated LDLR-KO and sham- treated LDLR-KO mice fed a Western diet for 6 weeks and compared the changes in gene expression in both groups to non-atherosclerotic CD animals.

ORGANISM(S): Mus musculus

PROVIDER: GSE30638 | GEO | 2011/07/14

SECONDARY ACCESSION(S): PRJNA144633

REPOSITORIES: GEO

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Attenuation of early atherogenesis in LDLR-KO mice by proteasome inhibition

Project description:To get further insights into the processes leading to attenuation of early stage atherosclerosis in the bortezomib treated LDLR-KO mice, microarray profiling of gene expression was performed on RNA taken from whole aortae of bortezomib treated LDLR-KO and sham- treated LDLR-KO mice fed a Western diet for 6 weeks and compared the changes in gene expression in both groups to non-atherosclerotic CD animals. Male 10-week-old LDLR-KO mice (B6.129S7-Ldlrtm1Her/J; JAX Mice, Boston) were fed a Western-type diet for 6 weeks ad libitum and received intraperitoneal injections of bortezomib (50 µg/kg body weight; WD+Bor) or saline (WD) twice weekly (n = 4). Mice that were fed normal diet served as chow diet control (CD; n = 4). Gene expression in aortic tissue was measured. Two independent experiments were performed.

2011-07-13 | E-GEOD-30638 | biostudies-arrayexpress

PCSK9 deficiency results in a specific shedding of excess LDLR in female mice only: Role of hepatic cholesterol

Project description:PCSK9 promotes the lysosomal degradation of cell surface LDL receptor (LDLR). We analyzed how excess LDLR generated by PCSK9 deficiency is differently handled in male and female mice to possibly unveil the mechanism leading to the lower efficacy of PCSK9 mAb on LDL-cholesterol levels in women. Analysis of intact or ovariectomized PCSK9 knockout (KO) mice supplemented with placebo or 17β-estradiol (E2) demonstrated that female, but not male mice massively shed the soluble ectodomain of the LDLR in the plasma. Liver-specific PCSK9 KO or alirocumab-treated WT mice exhibit the same pattern. This shedding is distinct from the basal one and is inhibited by ZLDI-8, a metalloprotease inhibitor pointing at ADAM10/ADAM17. In PCSK9 KO female mice, ZLDI- 8 raises by 80 % the LDLR liver content in a few hours. This specific shedding is likely cholesterol-dependent: it is prevented in PCSK9 KO male mice that exhibit low intra-hepatic cholesterol levels without activating SREBP-2, and enhanced by mevalonate or high cholesterol feeding, or by E2 known to stimulate cholesterol synthesis via the estrogen receptor-α. Liver transcriptomics demonstrates that critically low liver cholesterol in ovariectomized female or knockout male mice also hampers the cholesterol-dependent G2/M transition of the cell cycle. Finally, higher levels of shed LDLR were measured in the plasma of women treated with PCSK9 mAb. PCSK9 knockout female mice hormonally sustain cholesterol synthesis and shed excess LDLR, seemingly like women. In contrast, male mice rely on high surface LDLR to replenish their stocks, despite 80 % lower circulating LDL.

2022-09-22 | GSE205008 | GEO

The effect of ANGPTL3 mAb on liver transcriptomes in LDLR-deficient mice

Project description:Purpose: The goal of this study was to evaluate the effect of ANGPTL3 inhibition on liver transcriptomes in LDLR KO mice. Methods: Mice were treated once weekly for 3 weeks with 25mg/kg control mAb or ANGPTL3 mAb. Livers were harvested 6 days after the last mAb treatment. Results: ANGPTL3 inhibition had no major impact on hepatic gene expression.

2020-07-05 | GSE143726 | GEO

Bulk RNA-sequencing in Ldlr-/- or Ch25h-/-;Ldlr-/- peritoneal macrophages treated with LPS

Project description:Bulk RNA-sequencing in Ldlr-/- or Ch25h-/-;Ldlr-/- peritoneal macrophages treated with LPS

| PRJNA781469 | ENA

Single-nucleus RNA-seq of aortas from Ldlr-/- and Ldlr-/-Trem2-/- atherosclerotic mice

Project description:Single-nucleus RNA-seq of aortas was performed in Ldlr-/- and Ldlr-/-Trem2-/- mice fed a high fat diet for 10 weeks

2024-01-12 | GSE243086 | GEO

Bulk RNA-sequencing in Ldlr-/- or Ch25h-/-;Ldlr-/- peritoneal macrophages treated with LPS

Project description:Here we study the effect of LPS in the transcriptome of thioglycollate-elicited peritoneal macrophages isolated from Ldlr knock out and Ch25h;Ldlr double knock out mice

2022-07-01 | GSE189079 | GEO

Liver gene expression profiles of Tribbles-homolog1 (Trib1)/Ldl-receptor (Ldlr) double-knockout mice against Ldlr-knockout mice

Project description:Genetic variants at the TRIB1 (Tribbles-homolog 1) gene locus are strongly associated with plasma lipid traits and the risk of coronary artery disease in humans. In this study, we analyzed the consequences of Trib1-deficiency (Trib1-/-) on hepatic gene expression in mice on the atherosclerosis-susceptible LDL-receptor deficient (Ldlr-/-) background. Therefore, Trib1-/- mice were crossed onto the Ldlr-/- background to generate double knockout mice (Trib1-/-Ldlr-/-) and fed a semisynthetic, modified AIN76 diet (0.02% cholesterol, 4.3% fat). At 20 weeks of age, Trib1-/-Ldlr-/- mice and Trib1+/+Ldlr-/- control mice were sacrificed and liver tissue was snap frozen in liquid nitrogen and stored at -80°C until further processing. Total RNA was isolated from liver tissue (n=8 mice per genotype) and subjected to microarray gene expression analysis.

2023-03-15 | E-MTAB-12669 | biostudies-arrayexpress

Bulk RNA-sequencing in Ldlr-/- peritoneal macrophages treated with LPS

Project description:Bulk RNA-sequencing in Ldlr-/- peritoneal macrophages treated with LPS

| PRJNA713907 | ENA

Atlas of miRNome variations in different dyslipidemic conditions: a study in C57Bl/6, Ldlr-KO, and Pcsk9-KO mice.

Project description:In this study, mice with different genotypes and fed diets with different lipid content were enrolled, aiming to set up an atlas of miRNA expression levels in different organs with a relevant role in lipid/lipoprotein metabolism. Specifically, three genotypes were investigated: C57Bl/6 mice as controls, together with mice knock-out (KO) for LDLr (low-density lipoprotein receptor) and for PCSK9 (proprotein convertase subtilisin/kexin type 9). LDLr and PCSK9 are both involved in LDL turnover, the former mediating LDL clearance [PMID: 19299327], the latter causing the degradation of the LDLr protein [PMID: 17080197]. As a result, LDLrKO mice, because of their impaired LDL catabolism, are hypercholesterolemic and prone to atherosclerosis development, particularly when fed high-fat, cholesterol-containing diets [PMID: 8349823; PMID: 8182121]. On the contrary, PCSK9KO mice, characterized by an accelerated LDL catabolism, are hypocholesterolemic and atherosclerosis resistant [PMID: 15805190]. miRNA expression was investigated in liver, intestine, aorta, white adipose tissue and brain of mice on both standard and Western diet.

2023-09-06 | GSE227578 | GEO

MicroRNAs are Transported in Plasma and Delivered to Recipient Cells by High-Density Lipoproteins (Mouse HDL signatures from WT and LDLR-/- high fat diet)

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. Mouse HDL signatures from WT and LDLR-/- high fat diet Profiled HDL miRNA Signatures from N=4 WT; n=5 LDLR-/- HF mice

2011-03-23 | E-GEOD-25150 | biostudies-arrayexpress

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