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Identification of Gene Expression Changes in the Aorta of ApoE Null Mice Fed a High-Fat Diet.

ABSTRACT: Atherosclerosis is a chronic multifactorial inflammatory disease with high worldwide prevalence, and has become the leading cause of death. In the present study, we analyzed global gene expression changes in the aorta of Apolipoprotein E (ApoE) null mice fed a high-fat diet by using RNA-seq. We identified a total of 280 differentially expressed genes, of which 163 genes were upregulated and 117 genes were downregulated by high-fat diet compared with normal diet. Functional clustering and gene network analysis revealed that fatty acid metabolic process is crucial for atherosclerosis. By examining of the promoter regions of differentially expressed genes, we identified four causal transcription factors. Additionally, through connectivity map (CMap) analysis, multiple compounds were identified to have anti-atherosclerotic effects due to their ability to reverse gene expression during atherosclerosis. Our study provides a valuable resource for in-depth understanding of the mechanism underlying atherosclerosis.

SUBMITTER: Xi D

PROVIDER: S-EPMC5664139 | biostudies-literature | 2017 Oct

REPOSITORIES: biostudies-literature

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Identification of Gene Expression Changes in the Aorta of ApoE Null Mice Fed a High-Fat Diet.

Xi Dan D Zhao Jinzhen J Zhao Miao M Fu Weijun W Guo Zhigang Z Chen Hui H

Genes 20171024 10

Atherosclerosis is a chronic multifactorial inflammatory disease with high worldwide prevalence, and has become the leading cause of death. In the present study, we analyzed global gene expression changes in the aorta of Apolipoprotein E (ApoE) null mice fed a high-fat diet by using RNA-seq. We identified a total of 280 differentially expressed genes, of which 163 genes were upregulated and 117 genes were downregulated by high-fat diet compared with normal diet. Functional clustering and gene ne ...[more]

PMID: 29064389

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Project description:Atherosclerosis and its associated cardiovascular diseases (CVDs) are serious threats to human health and have been reported to be associated with the gut microbiota. Recently, the role of berberine (BBR) in atherosclerosis and gut microbiota has begun to be appreciated. The purposes of this study were to observe the effects of high or low doses of BBR on atherosclerosis and gut microbiota modulation, and to explore their correlation in ApoE-/- mice fed a high-fat diet. A significant decrease in atherosclerotic lesions was observed after treatment with BBR, with the effect of the high dose being more obvious. Both BBR treatments significantly reduced total cholesterol, APOB100, and very low-density lipoprotein cholesterol levels but levels of high/low-density lipoprotein cholesterol and lipoprotein (a) were only reduced by high-dose BBR. Decreased pro-inflammatory cytokines tumor necrosis factor-alpha, interleukin (IL)-1?, IL-6 and increased anti-inflammatory IL-10 and adiponectin levels were observed in the high-dose BBR group, but no decrease in IL-6 or increase in IL-10 was evident using the low-dose of BBR. 16S rRNA sequencing showed that BBR significantly altered the community compositional structure of gut microbiota. Specifically, BBR enriched the abundance of Roseburia, Blautia, Allobaculum, Alistipes, and Turicibacter, and changed the abundance of Bilophila. These microbiota displayed good anti-inflammatory effects related to the production of short-chain fatty acids (SCFAs) and were related to glucolipid metabolism. Alistipes and Roseburia were significantly enriched in high-dose BBR group while Blautia and Allobaculum were more enriched in low-dose, and Turicibacter was enriched in both BBR doses. Metagenomic analysis further showed an elevated potential for lipid and glycan metabolism and synthesis of SCFAs, as well as reduced potential of TMAO production after BBR treatment. The findings demonstrate that both high and low-dose BBR can improve serum lipid and systemic inflammation levels, and alleviate atherosclerosis induced by high-fat diet in ApoE-/- mice. The effects are more pronounced for the high dose. This anti-atherosclerotic effect of BBR may be partly attributed to changes in composition and functions of gut microbiota which may be associated with anti-inflammatory and metabolism of glucose and lipid. Notably, gut microbiota alterations showed different sensitivity to BBR dose.

Project description:BackgroundToll-like receptor-2 (TLR2) promotes vascular smooth muscle cell (VSMC) transdifferentiation to chondrocytes and calcification in a p38 MAPK-dependent manner. Vascular 5-methoxytryptophan (5-MTP) is a newly identified factor with anti-inflammatory actions. As 5-MTP targets p38 MAPK for its actions, we postulated that 5-MTP protects against vascular chondrogenesis and calcification.MethodsHigh-fat diet-induced advanced atherosclerosis in mice were performed to investigate the effect of 5-MTP on atherosclerotic lesions and calcification. VSMCs were used to determine the role of 5-MTP in VSMC chondrogenic differentiation and calcification. Alizarin red S and Alcian blue staining were used to measure VSMC calcification and chondrogenic differentiation, respectively.Results5-MTP was detected in aortic tissues of ApoE-/- mice fed control chow. It was reduced in ApoE-/- mice fed high-fat diet (HFD), but was restored in ApoE-/-Tlr2-/- mice, suggesting that HFD reduces vascular 5-MTP production via TLR2. Intraperitoneal injection of 5-MTP or its analog into ApoE-/- mice fed HFD reduced aortic atherosclerotic lesions and calcification which was accompanied by reduction of chondrogenesis and calcium deposition. Pam3CSK4 (Pam3), ligand of TLR2, induced SMC phenotypic switch to chondrocytes. Pretreatment with 5-MTP preserved SMC contractile proteins and blocked Pam3-induced chondrocyte differentiation and calcification. 5-MTP inhibited HFD-induced p38 MAPK activation in vivo and Pam3-induced p38 MAPK activation in SMCs. 5-MTP suppressed HFD-induced CREB activation in aortic tissues and Pam3-induced CREB and NF-κB activation in SMCs.ConclusionsThese findings suggest that 5-MTP is a vascular arsenal against atherosclerosis and calcification by inhibiting TLR2-mediated SMC phenotypic switch to chondrocytes and the consequent calcification. 5-MTP exerts these effects by blocking p38 MAPK activation and inhibiting CREB and NF-κB transactivation activity.

Dataset Information

Identification of Gene Expression Changes in the Aorta of ApoE Null Mice Fed a High-Fat Diet.

Publications

Identification of Gene Expression Changes in the Aorta of ApoE Null Mice Fed a High-Fat Diet.

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