Unknown,Transcriptomics,Genomics,Proteomics

Dataset Information

Changes in miR expression profile carotid plaques induced by acutely induced flow disturbances in apoe-/- mice on a high fat diet.

ABSTRACT: Atherosclerosis is causally related to disturbed flow through low and oscillatory shear stress. In order to study the miR expression profile in atherosclerotic plaques induced by disturbed flow, partial ligation of the carotid artery was performed. This procedure results acutely in severly reduced blood flow and in stenotic lesion formation within 6 weeks in apoe-/- mice on a high fat diet. We compared the miR expression profile in partially ligated left carotid arteries with the untreated right carotid artery to identify miRs which are involved in plaque formation through flow disturbances. The left carotid arteries of 6 female apoe-/- mice (6-8 weeks) were partially ligated (i.e. the external and internal carotid artery as well as the occipital artery were occluded; blood flow out of the common carotid artery occurs mainly through the superior thyroid artery). Following partial ligation the animals were fed a high fat diet for 6 weeks. Total RNA was isolated from partially ligated left carotid arteries and untreated right carotid arteries (control). MiRs expression profile of the partially ligated carotid arteries were compared with the control group. Biological replicates: 6 per group. One replicate per array.

ORGANISM(S): Mus musculus

SUBMITTER: Andreas Schober

PROVIDER: E-GEOD-26555 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Publications

MicroRNA-155 promotes atherosclerosis by repressing Bcl6 in macrophages.

Nazari-Jahantigh Maliheh M Wei Yuanyuan Y Noels Heidi H Akhtar Shamima S Zhou Zhe Z Koenen Rory R RR Heyll Kathrin K Gremse Felix F Kiessling Fabian F Grommes Jochen J Weber Christian C Schober Andreas A

The Journal of clinical investigation 20121008 11

Macrophages in atherosclerotic plaques drive inflammatory responses, degrade lipoproteins, and phagocytose dead cells. MicroRNAs (miRs) control the differentiation and activity of macrophages by regulating the signaling of key transcription factors. However, the functional role of macrophage-related miRs in the immune response during atherogenesis is unknown. Here, we report that miR-155 is specifically expressed in atherosclerotic plaques and proinflammatory macrophages, where it was induced by ...[more]

PMID: 23041630

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Project description:Atherosclerosis preferentially occurs in arterial regions of disturbed blood flow (d-flow), which alters gene expression, endothelial function, and atherosclerosis. Here, we show that d-flow regulates genome-wide DNA methylation patterns in a DNA methyltransferase (DNMT)-dependent manner. D-flow induced expression of DNMT1 in mouse arterial endothelium in vivo and in cultured endothelial cells by oscillatory shear (OS) in vitro. The DNMT inhibitor 5-Aza-2’deoxycytidine (5Aza) or DNMT1 siRNA significantly reduced OS-induced endothelial inflammation. Moreover, 5Aza reduced lesion formation in two ApoE-/- mouse atherosclerosis models. To identify the 5Aza mechanisms, we conducted two genome-wide studies: reduced representation bisulfite sequencing (RRBS) and microarray using endothelial-enriched gDNA and RNA, respectively, from the partially-ligated left carotid artery (LCA exposed to d-flow) and the right contralateral control (RCA) of mice treated with 5Aza or vehicle. Systems biological analyses using RRBS and transcriptome data revealed 11 mechanosensitive genes whose promoters were hypermethylated under d-flow conditions, but rescued by 5Aza treatment. Of those, the two transcription factors HoxA5 and Klf3 contain cAMP- response-elements, and their methylation status could serve as a mechanosensitive master switch in gene expression. Our results demonstrate that d-flow controls epigenomic DNA methylation patterns in a DNMT-dependent manner, which in turn alters endothelial gene expression and induces atherosclerosis. We used 6- to 8-week-old male C57Bl/6 mice (The Jackson Laboratory) according to the approved Institutional Animal Care and Use Committee protocol by Emory University. Mice were subjected to partial carotid ligation surgery under anesthesia. Brieﬂy, 3 of 4 caudal branches of LCA (left external carotid, internal carotid, and occipital artery) were ligated with 6-0 silk suture, although the superior thyroid artery was left intact. Development of low and oscillatory blood flow in the Left Carotid Artery of each mouse was determined by ultrasound measurements. Each sample contained total RNA from 3 pooled RCAs or LCAs. We ran 3 samples of LCA, RCA, AzaLCA, and AzaRCA on 2 microarrays.

Dataset Information

Changes in miR expression profile carotid plaques induced by acutely induced flow disturbances in apoe-/- mice on a high fat diet.

Publications

MicroRNA-155 promotes atherosclerosis by repressing Bcl6 in macrophages.

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