Unknown,Transcriptomics,Genomics,Proteomics

Dataset Information

Deletion of hyaluronan synthase 3 inhibits neointimal hyperplasia

ABSTRACT: Affymetrix Mouse Gene 2.0 ST Gene Expression Microarrays were used to analyze differentially expressed genes after carotid artery ligation. The aim of this experiment was to detect genes regulated in Has3 deficient as compared to wildtype controls that might be involved in neointimal hyperplasia. Neointimal hyperplasia was induced in female Has3 deficient mice and wildtype controls by ligation of the left common carotid artery. Carotid transcriptome was analyzed 5 days after surgery in ligated and non-ligated carotid arteries.

ORGANISM(S): Mus musculus

SUBMITTER: Rene Deenen

PROVIDER: E-GEOD-70410 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Publications

Deletion of Hyaluronan Synthase 3 Inhibits Neointimal Hyperplasia in Mice.

Kiene Lena S LS Homann Susanne S Suvorava Tatsiana T Rabausch Berit B Müller Julia J Kojda Georg G Kretschmer Inga I Twarock Sören S Dai Guang G Deenen René R Hartwig Sonja S Lehr Stefan S Köhrer Karl K Savani Rashmin C RC Grandoch Maria M Fischer Jens W JW

Arteriosclerosis, thrombosis, and vascular biology 20151119 2

<h4>Objective</h4>Hyaluronan (HA) is a polymeric glucosaminoglycan that forms a provisional extracellular matrix in diseased vessels. HA is synthesized by 3 different HA synthases (HAS1, HAS2, and HAS3). Aim of this study was to unravel the role of the HAS3 isoenzyme during experimental neointimal hyperplasia.<h4>Approach and results</h4>Neointimal hyperplasia was induced in Has3-deficient mice by ligation of the carotid artery. HA in the media of Has3-deficient mice was decreased 28 days after ...[more]

PMID: 26586662

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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

Deletion of hyaluronan synthase 3 inhibits neointimal hyperplasia

Publications

Deletion of Hyaluronan Synthase 3 Inhibits Neointimal Hyperplasia in Mice.

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