Identification of Key Genes Associated with Macrophage Autophagy in ApoE-/- Mice Atherosclerosis by Aortic Gene Expression Profile
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE232472 | GEO | 2024/01/04
REPOSITORIES: GEO
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Project description:Tertiary lymphoid organs (TLOs) emerge in response to nonresolving inflammation but their roles in adaptive immunity remain unknown. Here, we explored artery TLOs (ATLOs) to delineate atherosclerosis T cell responses in apoe-/- mice during aging. Though the T cell repertoire showed systemic age-associated contractions in size and modifications in subtype composition and activation, wt and apoe-/- mice were equally affected. In contrast, ATLOs - but not wt aortae, apoe-/- aorta segments without ATLOs or atherosclerotic plaques - promoted T cell recruitment, altered characteristics of T cell motility, primed and imprinted T cells in situ, generated CD4+/FoxP3-, CD4+/FoxP3+, CD8+/FoxP3- effector and central memory cells, and converted naïve CD4+/FoxP3- T cells into induced Treg cells. ATLOs also showed substantially increased antigen presentation capability by conventional dendritic cells (DCs) and monocyte-derived DCs but not by plasmacytoid DCs. Thus, the senescent immune system specifically employs ATLOs to control dichotomic atherosclerosis T cell immune responses. We assembled transcriptome maps of wt and apoe-/- aortae and aorta-draining RLNs and identified ATLOs as major sites of atherosclerosis-specific T cell responses during aging: Transcriptome atlases of wt and apoe-/- abdominal aortae and associated draining RLNs were constructed from laser capture microdissection (LCM)-based whole genome mRNA expression microarrays yielding 6 maps: wt adventitia (tissue-1); wt RLN (tissue-2); apoe-/- ATLOs (tissue-3); apoe-/- RLN (tissue-4); apoe-/- adventitia without adjacent plaques (tissue-5), and plaques (tissue-6). Several two-tissue comparisons within the transcriptome atlases are noteworthy: Unexpectedly, transcriptomes of wt and apoe-/- RLNs were virtually identical; additonal data revealed that transcriptomes of RLNs were strikingly similar to those of inguinal LNs which do not drain the aorta adventitia (as shown of India ink injection experiments of surgically exposed aortae); in sharp contrast, wt adventitia versus ATLOs revealed 1405 differentially expressed transcripts many of which encoded members of GO terms immune response and inflammatory response; the ATLO-plaque comparison also showed > 1000 differentially expressed transcripts; however, wt adventitia versus apoe-/- adventitia without plaque showed few genes (< 5 % of differentially expressed transcripts of the wt adventitia-ATLO comparison). Thus, the aorta transcriptome atlases support the conclusion that neither aorta-draining apoe-/- RLNs nor ILNs participate in atherosclerosis-specific T cell responses. In addition, they demonstrate that T cell responses in the diseased aorta are highly territorialized. Finally, these data show that the immune responses carried out in ATLOs differ significantly from those carried out in plaques. We next identified three major clusters within the transcriptome atlases through ANOVA analyses and application of strict filters: An adventitia cluster, a plaque/ATLO cluster, and a LN/plaque cluster. The total number of differentially expressed genes in each cluster were examined for GO terms immune response, inflammatory response, T cell activation, positive regulation of T cell response, and T cell proliferation. Within the adventitia cluster, similarities of transcriptomes of wt adventitia and apoe-/- adventitia without associated plaque versus ATLOs indicate that a robust number of immune response-regulating genes are selectively expressed in ATLOs which are located within a distance of few µm of the adventitia without associated plaques indicating a very high degree of territoriality of the atherosclerosis T cell response. Furthermore, unlike the total number of differentially regulated transcripts, the majority of transcripts among GO terms immune response and inflammatory response, was up-regulated. Inspection of the plaque/ATLO cluster provided further information: The majority of immune response regulating genes where expressed at a higher level in ATLOs when compared to plaques though plaques also contained a significant number of immune response regulating genes; the reverse is true for genes regulating inflammation. Finally, the lymph node cluster revealed that though the majority of immune response regulating genes resides in both wt and apoe-/- RLNs (with little differences between them) ATLOs express a selected set of immune response regulating genes at a higher level when compared to LNs. In addition, the inflammatory component of ATLOs when compared to LNs is documented by the finding that many more genes regulating inflammation reside in ATLOs even when compared to those of plaques. Key words: T cell response in atherosclerosis; Laser capture microdissection; transcriptome atlas of atherosclerosis. Citations: Gräbner R. et al. Lymphotoxin beta receptor signaling promotes tertiary lymphoid organogenesis in the aorta adventitia of aged ApoE-/- mice. J Exp Med 2009 Jan 16;206(1):233-48. PMID: 19139167; Moos M. et al. The lamina adventitia is the major site of immune cell accumulation in standard chow-fed apolipoprotein E-deficient mice. Arterioscler Thromb Vasc Biol. 2005 Nov;25(11):2386-91. Epub 2005 Sep 22. PMID: 16179593; Beer M. et al. Laser-capture microdissection of hyperlipidemic/ApoE-/- mouse aorta atherosclerosis. Methods Mol Biol. 2011;755:417-28. PMID: 21761324; Weih F. et al. Control of Dichotomic Innate and Adaptive Immune Responses by Artery Tertiary Lymphoid Organs in Atherosclerosis. Front Physiol. 2012;3:226. Epub 2012 Jul 6. PMID: 22783198. Wild-type and apoE-deficient mice on the C57BL/6J genetic background were maintained on a standard mouse chow. Total aortae were removed at the age of 6 (n=3), 32 (n=3), or 78 (n=3) w and microarrays were prepared from total RNA extracts or extracts of atherosclerotic lesions and adventitiae obtained by the use of a laser dissection microscope. In addition, aorta associated LNs or distant LNs were prepared from both mouse genotypes.
2013-10-30 | E-GEOD-40156 | biostudies-arrayexpress
Project description:This study compared gene expression in smooth muscle cells (SMCs) in atherosclerosis-prone and atherosclerosis-resistant aorta segments in 4 months old apolipoprotein E-deficient (apoE-/-) mice before plaque development. In a parallel experiment, both regions were compared in young C57Bl/6 mice. Aortas of 3 male and 3 female ApoE-/- mice were isolated, perfused with triton X-100 to remove endothelial cells and divided in an atherosclerosis-prone region (AA: ascending aorta, aortic arch and proximal 2 mm of thoracic aorta) and a resistant region (TA: central thoracic aorta, i.e. 6 mm distal from the proximal 2 mm). Microarray analysis (VIB-MAF) of pooled total RNA showed differential expression (>2-fold difference) for 244 genes. Up- or downregulation in the AA was observed for 186 and 58 genes respectively. Differential expression of 6 genes was confirmed using real-time PCR. The 201 genes that showed exclusively differential expression in apoE-/- mice were related to processes involved in atherosclerosis, such as cell adhesion, proliferation, differentiation, motility and death, lipid metabolism and immune responses. Furthermore, the transcription profile of the AA was in accordance with a more synthetic SMC phenotype. These results point to an altered transcriptome in SMCs in the aorta of apoE-/- mice at the atherosclerosis-prone location before actual lesion development. This suggests that SMCs, in addition to endothelial cells, can facilitate plaque formation at predilection sites. Experiment Overall Design: samples were hyrbidized in dye-swap.
2009-05-27 | E-GEOD-13836 | 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. 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:This series represents a comparison of gene expression in mouse aorta from MyD88-/-, apoE-/- mice versus apoE-/- control mice fed a high fat diet for 8 weeks, causing atherosclerotic lesion development. 5 MyD88-/-, apoE-/- mice were compared to 5 apoE-/- control mice and dye swap replicated for a total of 10 replicate microarrays. Keywords = Mus musculus Keywords = aorta Keywords = atherosclerosis Keywords = MyD88
2010-06-09 | E-GEOD-1058 | biostudies-arrayexpress
Project description:This study compared gene expression in smooth muscle cells (SMCs) in atherosclerosis-prone and atherosclerosis-resistant aorta segments in 4 months old apolipoprotein E-deficient (apoE-/-) mice before plaque development. In a parallel experiment, both regions were compared in young C57Bl/6 mice. Aortas of 3 male and 3 female ApoE-/- mice were isolated, perfused with triton X-100 to remove endothelial cells and divided in an atherosclerosis-prone region (AA: ascending aorta, aortic arch and proximal 2 mm of thoracic aorta) and a resistant region (TA: central thoracic aorta, i.e. 6 mm distal from the proximal 2 mm). Microarray analysis (VIB-MAF) of pooled total RNA showed differential expression (>2-fold difference) for 244 genes. Up- or downregulation in the AA was observed for 186 and 58 genes respectively. Differential expression of 6 genes was confirmed using real-time PCR. The 201 genes that showed exclusively differential expression in apoE-/- mice were related to processes involved in atherosclerosis, such as cell adhesion, proliferation, differentiation, motility and death, lipid metabolism and immune responses. Furthermore, the transcription profile of the AA was in accordance with a more synthetic SMC phenotype. These results point to an altered transcriptome in SMCs in the aorta of apoE-/- mice at the atherosclerosis-prone location before actual lesion development. This suggests that SMCs, in addition to endothelial cells, can facilitate plaque formation at predilection sites.
2009-05-15 | GSE13836 | GEO
Project description:Tertiary lymphoid organs (TLOs) emerge in response to nonresolving inflammation but their roles in adaptive immunity remain unknown. Here, we explored artery TLOs (ATLOs) to delineate atherosclerosis T cell responses in apoe-/- mice during aging. Though the T cell repertoire showed systemic age-associated contractions in size and modifications in subtype composition and activation, wt and apoe-/- mice were equally affected. In contrast, ATLOs - but not wt aortae, apoe-/- aorta segments without ATLOs or atherosclerotic plaques - promoted T cell recruitment, altered characteristics of T cell motility, primed and imprinted T cells in situ, generated CD4+/FoxP3-, CD4+/FoxP3+, CD8+/FoxP3- effector and central memory cells, and converted naïve CD4+/FoxP3- T cells into induced Treg cells. ATLOs also showed substantially increased antigen presentation capability by conventional dendritic cells (DCs) and monocyte-derived DCs but not by plasmacytoid DCs. Thus, the senescent immune system specifically employs ATLOs to control dichotomic atherosclerosis T cell immune responses. We assembled transcriptome maps of wt and apoe-/- aortae and aorta-draining RLNs and identified ATLOs as major sites of atherosclerosis-specific T cell responses during aging: Transcriptome atlases of wt and apoe-/- abdominal aortae and associated draining RLNs were constructed from laser capture microdissection (LCM)-based whole genome mRNA expression microarrays yielding 6 maps: wt adventitia (tissue-1); wt RLN (tissue-2); apoe-/- ATLOs (tissue-3); apoe-/- RLN (tissue-4); apoe-/- adventitia without adjacent plaques (tissue-5), and plaques (tissue-6). Several two-tissue comparisons within the transcriptome atlases are noteworthy: Unexpectedly, transcriptomes of wt and apoe-/- RLNs were virtually identical; additonal data revealed that transcriptomes of RLNs were strikingly similar to those of inguinal LNs which do not drain the aorta adventitia (as shown of India ink injection experiments of surgically exposed aortae); in sharp contrast, wt adventitia versus ATLOs revealed 1405 differentially expressed transcripts many of which encoded members of GO terms immune response and inflammatory response; the ATLO-plaque comparison also showed > 1000 differentially expressed transcripts; however, wt adventitia versus apoe-/- adventitia without plaque showed few genes (< 5 % of differentially expressed transcripts of the wt adventitia-ATLO comparison). Thus, the aorta transcriptome atlases support the conclusion that neither aorta-draining apoe-/- RLNs nor ILNs participate in atherosclerosis-specific T cell responses. In addition, they demonstrate that T cell responses in the diseased aorta are highly territorialized. Finally, these data show that the immune responses carried out in ATLOs differ significantly from those carried out in plaques. We next identified three major clusters within the transcriptome atlases through ANOVA analyses and application of strict filters: An adventitia cluster, a plaque/ATLO cluster, and a LN/plaque cluster. The total number of differentially expressed genes in each cluster were examined for GO terms immune response, inflammatory response, T cell activation, positive regulation of T cell response, and T cell proliferation. Within the adventitia cluster, similarities of transcriptomes of wt adventitia and apoe-/- adventitia without associated plaque versus ATLOs indicate that a robust number of immune response-regulating genes are selectively expressed in ATLOs which are located within a distance of few µm of the adventitia without associated plaques indicating a very high degree of territoriality of the atherosclerosis T cell response. Furthermore, unlike the total number of differentially regulated transcripts, the majority of transcripts among GO terms immune response and inflammatory response, was up-regulated. Inspection of the plaque/ATLO cluster provided further information: The majority of immune response regulating genes where expressed at a higher level in ATLOs when compared to plaques though plaques also contained a significant number of immune response regulating genes; the reverse is true for genes regulating inflammation. Finally, the lymph node cluster revealed that though the majority of immune response regulating genes resides in both wt and apoe-/- RLNs (with little differences between them) ATLOs express a selected set of immune response regulating genes at a higher level when compared to LNs. In addition, the inflammatory component of ATLOs when compared to LNs is documented by the finding that many more genes regulating inflammation reside in ATLOs even when compared to those of plaques. Key words: T cell response in atherosclerosis; Laser capture microdissection; transcriptome atlas of atherosclerosis. Citations: Gräbner R. et al. Lymphotoxin beta receptor signaling promotes tertiary lymphoid organogenesis in the aorta adventitia of aged ApoE-/- mice. J Exp Med 2009 Jan 16;206(1):233-48. PMID: 19139167; Moos M. et al. The lamina adventitia is the major site of immune cell accumulation in standard chow-fed apolipoprotein E-deficient mice. Arterioscler Thromb Vasc Biol. 2005 Nov;25(11):2386-91. Epub 2005 Sep 22. PMID: 16179593; Beer M. et al. Laser-capture microdissection of hyperlipidemic/ApoE-/- mouse aorta atherosclerosis. Methods Mol Biol. 2011;755:417-28. PMID: 21761324; Weih F. et al. Control of Dichotomic Innate and Adaptive Immune Responses by Artery Tertiary Lymphoid Organs in Atherosclerosis. Front Physiol. 2012;3:226. Epub 2012 Jul 6. PMID: 22783198.
2013-10-30 | GSE40156 | 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:Microarray gene expression profiling of aorta genes of APOE-deficient mice receiving atherosclerosis treatment with the ACE inhibitor captopril. Hypercholesterolemic APOE-deficient mice were used as a standard model of atherosclerosis to study gene expression changes during atherosclerosis treatment with the ACE inhibitor captopril. Microarray analysis was performed of whole aortas isolated from captopril-treated APOE-deficient mice relative to untreated APOE-deficient mice with overt atherosclerosis, and nontransgenic control mice. Microarray gene expression profiling revealed that captopril-mediated atherosclerosis prevention involved inhibition of aorta-infiltrating immune cells such as pro-atherogenic T lymphocytes and macrophages. Experiment Overall Design: Microarray gene expression profiling was performed of whole aortas isolated from APOE-deficient mice with atherosclerosis relative to captopril-treated APOE-deficient mice, and nontransgenic 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 angiotensin-converting enzyme (ACE) inhibitor, captopril (20 mg/kg in drinking water), and nontransgenic control C57BL/6J mice. Two biological replicates were made of each group, and total RNA of three aortas was pooled for one gene chip.
2009-12-14 | E-GEOD-19286 | biostudies-arrayexpress
Project description:This series represents a comparison of gene expression in mouse aorta from MyD88-/-, apoE-/- mice versus apoE-/- control mice fed a high fat diet for 8 weeks, causing atherosclerotic lesion development. 5 MyD88-/-, apoE-/- mice were compared to 5 apoE-/- control mice and dye swap replicated for a total of 10 replicate microarrays. Keywords = Mus musculus Keywords = aorta Keywords = atherosclerosis Keywords = MyD88 Keywords: other
2004-02-26 | GSE1058 | GEO
Project description:Microarray gene expression profiling of aorta genes of APOE-deficient mice receiving atherosclerosis treatment with the ACE inhibitor captopril. Hypercholesterolemic APOE-deficient mice were used as a standard model of atherosclerosis to study gene expression changes during atherosclerosis treatment with the ACE inhibitor captopril. Microarray analysis was performed of whole aortas isolated from captopril-treated APOE-deficient mice relative to untreated APOE-deficient mice with overt atherosclerosis, and nontransgenic control mice. Microarray gene expression profiling revealed that captopril-mediated atherosclerosis prevention involved inhibition of aorta-infiltrating immune cells such as pro-atherogenic T lymphocytes and macrophages.
2009-12-03 | GSE19286 | GEO