COL6A6 peptide vaccine ameliorates atherosclerosis through inducing immune response and regulating lipid metabolism in ApoE-/- mice
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PROVIDER: PRJNA1030016 | ENA |
REPOSITORIES: ENA
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Project description:Atherosclerosis is an autoimmune disease characterized by lipid imbalances and chronic inflammation within blood vessels with limited preventive and treatment options currently available. Previous experiments have demonstrated the atheroprotective potential of collagen 6 subtype alpha6 (COL6A6) in apolipoprotein E-deficient (ApoE-/-) mice with hyperlipidemia. However, the mechanism underlying the anti-atherosclerotic effects of COL6A6 remains elusive. This knowledge gap was addressed in the present study by immunizing ApoE-/- mice with the Pep_A6 vaccine, comprising a COL6A6 peptide-KLH (keyhole limpet hemocyanin) conjugate and aluminum (Alum) hydroxide adjuvant, and conducting a series of experiments. Our objective was to investigate the efficacy of the Pep_A6 vaccine, focusing on immune responses and lipid metabolism. Our finding showed that the Pep_A6 vaccine represents a novel approach to combat atherosclerosis by inducing a large increase in Treg cells, the generation of antigen-specific antibodies and regulating lipid metabolism.
2024-10-02 | GSE245813 | GEO
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:Enhanced prenatal fatty streak formation in human fetuses has been associated with maternal hypercholesterolemia. However, the possible roles of maternal genetic background and in utero environment on development of atherosclerosis in adult life have not been unraveled. We generated genetically identical heterozygous apoE-deficient mice offspring with a different maternal background to study the intrauterine effect of maternal genotype and associated hypercholesterolemia on the developing vascular system. As read out for increased atherosclerosis development in adult life, a constrictive collar was placed around the carotid artery to induce lesion formation. A significant increase in endothelial cell activation and damage was detected in the carotid arteries of heterozygous apoE-deficient fetuses with apoE-deficient mothers compared with offspring from wild type mothers, but no fatty streak formation was observed. Postnatally, all carotid arteries revealed normal morphology. In adult offspring with maternal apoE-deficiency, the constrictive collar resulted in severe lesion (9/10) development compared with no to only minor lesions (2/10) in offspring of wild type mothers. Microarray analysis showed no effect of maternal apoE-deficiency on gene expression in adult offspring. We conclude that maternal apoE-deficiency not only affects fetal arteries, but also increases the susceptibility for development of collar-induced atherosclerosis in adult life. Experiment Overall Design: Crossing of hypercholesterolemic female with normocholesterolemic male and vice versa, determination of susceptabilioty to atherosclerosis in offspring
2008-06-14 | E-GEOD-6134 | biostudies-arrayexpress
Project description:Background: Atherosclerosis leads high mortality, highlighting an urgent need for new therapeutic strategies. Protein kinases orchestrate multiple cellular events in atherosclerosis and may provide new therapeutic targets for atherosclerosis. Here, we identified a protein kinase, WEE1 G2 checkpoint kinase (WEE1), promoting inflammatory response in atherosclerosis. Methods: The ApoE-/- mice without macrophage-specific WEE1 deletion (ApoE-/-WEE1f/f) and ApoE-/- mice with macrophage-specific WEE1 deletion (ApoE-/-WEE1MCKO) were generated using bone marrow transplantation. These mice and WEE1 inhibitor MK1775 were used in a high-fat diet (HFD)-induced atherosclerotic model. Human atherosclerotic tissues, mouse primary peritoneal macrophages (MPMs), 293T cells, and recombinant proteins were utilized to investigate the pathogenic role and underlying mechanisms of WEE1. Results: We identified up-regulated p-WEE1 in macrophages in atherosclerotic lesions of HFD-fed ApoE-/- mice. Transcriptome sequencing analysis indicated that WEE1 promotes oxLDL-induced inflammation in macrophages. We then demonstrated that macrophage-specific deletion or pharmacological inhibition of WEE1 attenuates atherosclerosis by reducing inflammation both in vivo and in vitro. The overexpression of wild-type WEE1 or activating-mutant WEE1, but not inactivating-mutant WEE1, exacerbates inflammation in macrophages. Mechanistically, transcriptome sequencing analysis and co-immunoprecipitation followed by quantitative proteomics analysis identified p65 as a binding protein of WEE1. We confirmed that WEE1 directly interacts with the RHD domain of p65 via kinase domain and phosphorylates p65 at S536, thereby facilitating subsequent NF-κB activation and inflammatory response in macrophages. Conclusions: Our findings demonstrated that macrophage WEE1 promotes inflammatory atherosclerosis by directly binding to p65 and phosphorylate it at S536. This study provides WEE1 as a new p65 regulator in inflammation and a potential therapeutic target for atherosclerosis.
2024-03-25 | PXD050932 | Pride
Project description:Enhanced prenatal fatty streak formation in human fetuses has been associated with maternal hypercholesterolemia. However, the possible roles of maternal genetic background and in utero environment on development of atherosclerosis in adult life have not been unraveled. We generated genetically identical heterozygous apoE-deficient mice offspring with a different maternal background to study the intrauterine effect of maternal genotype and associated hypercholesterolemia on the developing vascular system. As read out for increased atherosclerosis development in adult life, a constrictive collar was placed around the carotid artery to induce lesion formation. A significant increase in endothelial cell activation and damage was detected in the carotid arteries of heterozygous apoE-deficient fetuses with apoE-deficient mothers compared with offspring from wild type mothers, but no fatty streak formation was observed. Postnatally, all carotid arteries revealed normal morphology. In adult offspring with maternal apoE-deficiency, the constrictive collar resulted in severe lesion (9/10) development compared with no to only minor lesions (2/10) in offspring of wild type mothers. Microarray analysis showed no effect of maternal apoE-deficiency on gene expression in adult offspring. We conclude that maternal apoE-deficiency not only affects fetal arteries, but also increases the susceptibility for development of collar-induced atherosclerosis in adult life. Keywords: Atheroslcersosis development
2007-08-08 | GSE6134 | GEO
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:ApoE-/- atherosclerosis reversal
| PRJNA530042 | ENA
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:Background: Atherosclerosis leads high mortality, highlighting an urgent need for new therapeutic strategies. Protein kinases orchestrate multiple cellular events in atherosclerosis and may provide new therapeutic targets for atherosclerosis. Here, we identified a protein kinase, WEE1 G2 checkpoint kinase (WEE1), promoting inflammatory response in atherosclerosis. Methods: The ApoE-/- mice without macrophage-specific WEE1 deletion (ApoE-/-WEE1f/f) and ApoE-/- mice with macrophage-specific WEE1 deletion (ApoE-/-WEE1MCKO) were generated using bone marrow transplantation. These mice and WEE1 inhibitor MK1775 were used in a high-fat diet (HFD)-induced atherosclerotic model. Human atherosclerotic tissues, mouse primary peritoneal macrophages (MPMs), 293T cells, and recombinant proteins were utilized to investigate the pathogenic role and underlying mechanisms of WEE1. Results: We identified up-regulated p-WEE1 in macrophages in atherosclerotic lesions of HFD-fed ApoE-/- mice. Transcriptome sequencing analysis indicated that WEE1 promotes oxLDL-induced inflammation in macrophages. We then demonstrated that macrophage-specific deletion or pharmacological inhibition of WEE1 attenuates atherosclerosis by reducing inflammation both in vivo and in vitro. The overexpression of wild-type WEE1 or activating-mutant WEE1, but not inactivating-mutant WEE1, exacerbates inflammation in macrophages. Mechanistically, transcriptome sequencing analysis and co-immunoprecipitation followed by quantitative proteomics analysis identified p65 as a binding protein of WEE1. We confirmed that WEE1 directly interacts with the RHD domain of p65 via kinase domain and phosphorylates p65 at S536, thereby facilitating subsequent NF-κB activation and inflammatory response in macrophages. Conclusions: Our findings demonstrated that macrophage WEE1 promotes inflammatory atherosclerosis by directly binding to p65 and phosphorylate it at S536. This study provides WEE1 as a new p65 regulator in inflammation and a potential therapeutic target for atherosclerosis.
2024-03-30 | GSE262427 | GEO
Project description:Atherosclerosis development is largely driven by old age and lifestyle factors, such as diet, physical activity and smoking. Microarray analysis of skeletal muscle gene expression was performed on young (14 weeks) and aged (49-52 weeks) C57BL/6 wild-type (WT) and atherosclerosis-prone ApoE-/- mice, which were subjected to physical endurance exercise on a treadmill for 5 weeks, with or without a high fat diet.
2018-08-02 | E-MTAB-5685 | biostudies-arrayexpress