MRTF-A promotes angiotensin II-induced inflammatory response and aortic dissection in mice
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ABSTRACT:
PROVIDER: PRJNA576154 | ENA |
REPOSITORIES: ENA
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Project description:Aortic dissection (AD) is a major cause of acute aortic syndrome with high mortality due to the destruction of aortic walls. Although recent studies indicate the critical role of inflammation in the disease mechanism of AD, it is unclear how inflammatory response is initiated. Here, we demonstrate that myocardin-related transcription factor A (MRTF-A), a signal transducer of humoral and mechanical stress, plays an important role in pathogenesis of AD in a mouse model. A mouse model of AD was created by continuous infusion of angiotensin II (AngII) that caused dilation of thoracic aorta in 1 day and AD in 4 days. Systemic deletion of Mrtfa gene resulted in a marked suppression of AD development. Transcriptome and gene annotation enrichment analyses revealed that AngII infusion for 1 day caused pro-inflammatory and pro-apoptotic responses before AD development, which were suppressed by Mrtfa deletion. AngII infusion for 1 day induced pro-inflammatory response, as demonstrated by expressions of Il6, Tnf , and Ccl2, and apoptosis of aortic wall cells, as detected by TUNEL staining, in an MRTF-A-dependent manner. Furthermore, pharmacological inhibition of MRTF-A by CCG-203971 during AngII infusion prevented AD development, indicating that acute suppression of MRTF-A is effective in preventing the aortic wall destruction. These results indicate that MRTF-A transduces the stress of AngII challenge to the pro-inflammatory and pro-apoptotic responses, ultimately leading to AD development. Intervening this pathway may represent a potential therapeutic strategy.
2020-04-01 | GSE138484 | GEO
Project description:Aortic dissection (AD) is a major cause of acute aortic syndrome with high mortality due to the destruction of aortic walls. Although recent studies indicate the critical role of inflammation in the disease mechanism of AD, it is unclear how inflammatory response is initiated. Here, we demonstrate that myocardin-related transcription factor A (MRTF-A), a signal transducer of humoral and mechanical stress, plays an important role in pathogenesis of AD in a mouse model. A mouse model of AD was created by continuous infusion of angiotensin II (AngII) that induced MRTF-A expression and caused AD in 4 days. Systemic deletion of Mrtfa gene resulted in a marked suppression of AD development. Transcriptome and gene annotation enrichment analyses revealed that AngII infusion for 1 day caused pro-inflammatory and pro-apoptotic responses before AD development, which were suppressed by Mrtfa deletion. AngII infusion for 1 day induced pro-inflammatory response, as demonstrated by expressions of Il6, Tnf, and Ccl2, and apoptosis of aortic wall cells, as detected by TUNEL staining, in an MRTF-A-dependent manner. Pharmacological inhibition of MRTF-A by CCG-203971 during AngII infusion partially suppressed AD phenotype, indicating that acute suppression of MRTF-A is effective in preventing the aortic wall destruction. These results indicate that MRTF-A transduces the stress of AngII challenge to the pro-inflammatory and pro-apoptotic responses, ultimately leading to AD development. Intervening this pathway may represent a potential therapeutic strategy.
| S-EPMC7092993 | biostudies-literature
Project description:Aneurysmatic and dissection cells show a specific alteration of gene expression, which allow a disease specific distinction. We used microarrays to analyse the cellular gene expression of controls, thoracic aortic aneurysm, and aortic dissection.
2022-12-02 | GSE219204 | GEO
Project description:In this study we used microarrays to examine relative genes expression within the aorta of ApoE-/- infused with angiotensin II in relation to aneurysm formation. Infusion of angiotensin II induces aortic dilatation particularly of the suprarenal aorta in ApoE-/- mice. Based on studies carried out in our and other laboratories the response to angiotensin II is variable, with some mice developing large aneurysms but other animals appearing resistant to aneurysm formation with aortic diameters similar to that of saline controls. We compared RNA expression from whole aortas of 17 week old male ApoE-/- mice exposed to angiotensin II (1.44 µg/kg/min) for 4 weeks where there was clear evidence of aortic aneurysm formation (n=5) with that of mice failing to develop aneurysms (n=7) and those exposed to saline infusion (n=6). AAA was defined as diameter of suprarenal aorta greated than 1.5mm measured on photographs of aortas at necroscopy. Keywords: Disease state analysis 18 samples analysed, AAA (n=5), no AAA (n=7), saline (n=6). AAA - abdominal aortic aneurysm
2010-06-24 | E-GEOD-12591 | biostudies-arrayexpress
Project description:Genome wide DNA methylation profiling of ascending aorta tissue samples from normal, aortic dissection and bicuspid aortic valve patients with aortic dilation. The Illumina Infinium 450k Human DNA methylation Beadchip was used to obtain DNA methylation profiles across more than 450,000 CpGs in ascending aorta samples. Samples included 6 normal donors, 12 patients with aortic dissection and 6 patients with bicuspid aortic valve and dilated aorta.
2019-07-11 | GSE84274 | GEO
Project description:In this study we used microarrays to examine relative genes expression within the aorta of ApoE-/- infused with angiotensin II in relation to aneurysm formation. Infusion of angiotensin II induces aortic dilatation particularly of the suprarenal aorta in ApoE-/- mice. Based on studies carried out in our and other laboratories the response to angiotensin II is variable, with some mice developing large aneurysms but other animals appearing resistant to aneurysm formation with aortic diameters similar to that of saline controls. We compared RNA expression from whole aortas of 17 week old male ApoE-/- mice exposed to angiotensin II (1.44 µg/kg/min) for 4 weeks where there was clear evidence of aortic aneurysm formation (n=5) with that of mice failing to develop aneurysms (n=7) and those exposed to saline infusion (n=6). AAA was defined as diameter of suprarenal aorta greated than 1.5mm measured on photographs of aortas at necroscopy. Keywords: Disease state analysis
2009-08-26 | GSE12591 | GEO
Project description:The mechanisms of acute aortic dissection are not well understood. Transcriptomic strategy has been proven to be an effective way to find the potential mechanisms and also the reliable biomarkers for a specific disease. The whole-genome expression profiling was assayed in a panel of aortic tissues from 4 male acute aortic dissection patients and 4 male healthy controls.
2021-12-12 | GSE190635 | GEO
Project description:Rats (Wag/Rij, females) were chronically treated with Losartan (20mg/d), an angiotensin II-receptor blocker during 9 months. Gene expression profiling was performed on aortic media to understand the long-term effect of this molecule on the cardiovascular system.
2010-09-23 | GSE18298 | GEO
Project description:Objective-Aortic pathologies exhibit sexual dimorphism, with aneurysms in the ascending, thoracic and abdominal aorta (AAA) exhibiting higher prevalence in males. Despite lower incidence of aortic vascular disease in women, aneurysms progress rapidly. Mechanisms for these sex differences are unclear. We defined the role of sex chromosome complement and testosterone in regional development and progression of angiotensin II (AngII)-induced vascular pathologies. Approach and Results-We used transgenic male mice expressing Sry on an autosome to create low density lipoprotein receptor (Ldlr) deficient male mice with an XY or XX sex chromosome complement. Subjects were then sham operated or orcheictomized. Transcriptional profiling on abdominal aortas from XY or XX males demonstrated1746 genes influenced by sex chromosomes, sex hormones, or an interaction. A second cohort of animals was then infused with AngII for 28 days. Diffuse aortic aneurysm pathology developed in XY AngII-infused males, while XX males developed discrete AAAs. Castration reduced all AngII-induced aortic pathologies in XY and XX males. Thoracic aortas from AngII-infused XY males, but not XX males exhibited adventitial thickening. We infused male XY and XX mice with saline or AngII and quantified mRNA abundance of key genes in thoracic versus abdominal aortas. Regional differences in mRNA abundance existed before AngII infusions, which were differentially influenced by AngII between genotypes. Prolonged AngII infusions resulted in AAA aortic wall thickening in XY males with diffuse aortic pathology, while XX males had dilated focal AAAs. Conclusions-An XY sex chromosome complement mediates diffuse aortic pathology, while an XX sex chromosome complement contributes to discrete AngII-induced AAAs.
2018-07-22 | GSE102143 | GEO
Project description:We investigated the relationship between a developemnt of aortic dissection and inflammatory cells. Il-1b high expression macrophage contributed to developing an aortic dissection.
2024-03-01 | GSE224559 | GEO