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High salt intake exacerbates aortic dissection through IL-17 pathway

ABSTRACT: Rationale— Aortic dissection (AD) is a fatal disease that occurs suddenly without preceding clinical signs or symptoms. It is desirable to prevent AD before the onset. Although high salt intake is an established risk factor for cardiovascular diseases, the relationship between high salt intake and AD has not been clarified. Although recent studies have shown that high salt intake promotes interleukin (IL)-17-dependent inflammation, it is unknown whether this mechanism is involved in the pathogenesis of AD. Objective— The purpose of this study was to investigate the effect of high salt challenge on AD and involvement of IL-17. Methods and Results— We used a mouse AD model that was induced by continuous infusion of -aminopropionitrile and angiotensin II. High salt challenge exacerbated AD lesion length compared to the mice without high salt challenge, which was abolished in IL-17 knockout mice. Unexpectedly, deletion of IL-17 resulted in the activation of Smad pathway, induction of synthetic phenotype of smooth muscle cells, remodeling of extracellular matrix in aortic tunica media, reduced stiffness of aortic walls, and less stress-induced activation of NFkB. Conclusions— These findings establish the worsening effect of high salt intake on AD that involves IL-17 pathway through the extracellular matrix metabolism. Salt restriction may represent a low-cost and practical way to reduce AD risk.

ORGANISM(S): Mus musculus

PROVIDER: GSE116434 | GEO | 2018/12/31

REPOSITORIES: GEO

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High salt intake exacerbates aortic dissection through IL-17 pathway

Project description:High salt intake exacerbates aortic dissection through IL-17 pathway

| PRJNA478508 | ENA

Genetic Deletion of Socs3 in Smooth Muscle Cells Ameliorates Aortic Dissection in Mice

Project description:Objective—We aimed to elucidate how the inflammatory response is involved in AD progression and the associated tissue destruction, focusing on the role of Jak/Stat signaling in smooth muscle cells (SMCs). Background—Aortic dissection (AD) is caused by disruption of the intima-media complex and tearing of the medial layer of the aorta. AD is life-threatening due to progressive destruction of the aorta, resulting in critical damage to organs. Recent studies reveal that the inflammatory response, including Jak/Stat signaling, is important in AD pathogenesis. However, it remains unclear how Jak/Stat signaling is involved in the tissue destruction in AD. Methods—Immunohistochemical analysis of human AD tissue revealed activation of signal transducer and activator of transcription 3 (Stat3) in medial SMCs. Stat3 activation was recapitulated in a mouse model of AD induced via β-aminopropionitrile and angiotensin II infusion. We also created a knockout mouse strain (smSocs3-KO) by deleting Socs3, a negative regulator of Jak/Stat signaling, specifically in mouse SMCs. Results—Compared to wild-type mice, smSocs3-KO mice developed a less severe AD phenotype that was associated with proinflammatory response at baseline, increased fibroblast and collagen deposition, and reinforced aortic tensile strength. Cell culture experiments revealed that Stat3 activation in SMCs caused secretion of factors that can stimulate fibroblast growth. Conclusions—Our present findings suggested that, although an acute inflammatory response is detrimental in AD, chronic activation of the SMC-mediated proinflammatory response was protective against aortic destruction in AD.

2020-04-01 | GSE147078 | GEO

High salt reduces the activation of IL-4+IL-13 stimulated macrophages

Project description:High salt (NaCl) intake is a major risk factor for cardiovascular disease; high NaCl has also been shown to be a powerful modulator of pro-inflammatory immune cell polarization. To investigate the effect of high NaCl on the polarization of M(IL-4+IL-13) macrophages we performed gene expression analysis by microarray and genome wide histone modification (H3K4me3 and H4ac) analysis by ChIP-seq of murine bone marrow derived macrophages. Macrophages were polarized with recombinant IL-4 and IL-13 in vitro in the presence or absence of an additional 40mM of NaCl in the culture medium for 24h before analysis.

2015-02-07 | E-MTAB-3140 | biostudies-arrayexpress

High salt reduces the activation of IL-4+IL-13 stimulated macrophages

2014-12-16 | E-MTAB-3163 | biostudies-arrayexpress

Effect of rapamycin on gene expresssion in mouse model of aortic dissection

Project description:Aortic dissection (AD) is a medical emergency that leads to sudden death. Effective medical therapy is not available because molecular mechanism of AD is poorly understood. We performed the transcriptome analysis in mouse AD model that was created by infusion of beta-aminopropionitrile, a collagen crosslink inhibitor, and angiotensin II. Bayesian network analysis of the transcriptome revealed several distinct gene clusters that were tightly co-regulated during AD development. Functional annotation analysis revealed that each gene cluster has distinct function, namely, cell proliferation, inflammation, cell locomotion and adhesion, and muscle differentiation. Among the gene clusters, cell proliferation cluster was the first to be activated during AD development. Cell proliferation before AD development was confirmed by immunoblotting of G1 cyclins. Immunostaining for Ki67 and cell markers revealed the proliferation of smooth muscle cells, fibroblasts, and monocytes in aortic tissue before AD development. Treatment of mice with rapamycin, an mTOR inhibitor, suppressed cell proliferative response in AD model. Rapamycin completely prevented AD when given before AD development, and effectively suppressed progression when given after AD development. Interestingly, transcriptome analysis showed that rapamycin strongly suppressed cell proliferation and muscle differentiation clusters, but its effect on inflammation cluster was modest. We concluded that mTOR constitutes an essential part of the molecular pathogenesis of AD by regulating cell proliferation, and represents a new therapeutic target.

2020-04-01 | GSE138558 | GEO

MRTF-A promotes angiotensin II-induced inflammatory response and aortic dissection in mice

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

Comparative transcriptomic profiling of peripheral blood mononuclear cells (PBMNCs) isolated from pigs exposed to an atherogenic diet (AD) or to an AD supplemented with Grape Extract (GE) and/or Resveratrol (RES).

Project description:We used Affymetrix microarrays to investigate gene expression changes in PBMNCs isolated from female and male pigs to determine significant modulatory effects that may have been induced by the intake of GE and (or) RES during 4 months in animals fed an atherogenic diet (AD) . The aim of this work was to determine whether the intake of low doses of a Grape Extract (GE; 1 g/70 Kg animal body weight) and (or) Resveratrol (RES; 18 mg/70 Kg animal body weight) exerted any modulatory effects, at the level of gene expression, in PBMNCs isolated from female and male pigs exposed to an atherogenic diet (AD) for 4 months. We isolated PBMNCs, and the corresponding total RNA, from 2 female and 2 male pigs for each group. Pure RNA was extracted from the PBMNCs for microarrays analyses (Affymetrix) and gene differential expression determined between the AD fed animals and control (CT) animals (to determine the effects of a high-fat consumption) and between the AD fed animals supplemented with GE and (or) RES and the animals fed the AD diet alone (to determine the effects of GE and (or) RES on the fat consumption). In addition, the effects of the consumption of GE and RES against a standard control diet (CT) were also determined. Differential gene expression: 1) AD vs CT (response to exposure to a high-fat diet); 2) AD-GE vs AD (modulatory effects of the intake of a grape extract on high-fat fed animals); 3) AD-GE-RES vs AD (modulatory effects of the intake of a resveratrol-enriched grape extract on high-fat fed animals); 4) AD-RES vs AD (modulatory effects of the intake of resveratrol on high-fat fed animals); 5) CT-GE-RES vs CT (modulatory effects of the intake of a resveratrol-enriched grape extract on animals fes a standard pig chow).

2011-07-22 | E-GEOD-30874 | biostudies-arrayexpress

Expression data from the aortas of ApoE knockout and ApoE/IL-17 double knockout mice

Project description:Interleukin-17 (IL-17)-secreting T helper 17 cells (Th17) are a recently identified CD4+ T helper subset that has been implicated in various inflammatory and autoimmune diseases. The issue of whether interleukin-17A (IL-17) contributes to hyperlipidemia-induced aortic endothelial cell activation remained unknown. Here, we reported that IL-17 contributes to hyperlipidemia-induced modulation of vascular cell gene expression during early atherosclerosis in vivo. Our results has shed lights onto the role of IL-17 on EC biology and has provided important insights for future development of novel therapeutics for early intervention of cardiovascular diseases and other inflammatory diseases.

2015-10-11 | GSE73907 | GEO

The role of macrophage Socs3 in the pathogenesis of aortic dissection

Project description:Background—Aortic dissection (AD) is a life-threatening medical emergency caused by the abrupt destruction of the intimomedial layer of the aortic walls. As previous studies have reported the involvement of proinflammatory cytokine IL-6 in AD pathogenesis, we investigated the role of Stat3 signaling, a downstream pathway of IL-6 in macrophages in pathogenesis of AD. Methods and Results—We characterized the pathological and molecular events triggered by aortic stress, which can lead to AD. Aortic stress on the suprarenal aorta due to infrarenal aorta stiffening and angiotensin II infusion for 1 week caused focal medial rupture at the branching point of the celiac trunk and superior mesenteric artery. This focal medial rupture in 6 weeks in wild type (WT) mice but progressed to AD in mice with macrophage-specific deletion of Socs3 gene (mSocs3-KO). mSocs3-KO mice showed premature activation of cell proliferation, an inflammatory response, and skewed differentiation of macrophages toward the tissue-destructive phenotype. Concomitantly, they showed aberrant phenotypic modulation of SMCs and TGFβ signaling, which are likely to participate in tissue repair. Human AD samples revealed STAT3 activation in adventitial macrophages adjacent to the site of tissue destruction. Conclusions—These findings suggest that AD development is preceded by focal medial rupture, in which macrophage Socs3 maintains proper inflammatory response and differentiation of SMCs, thus promoting fibrotic healing to prevent tissue destruction and AD development. Understanding the sequence of the pathological and molecular events preceding AD development will help predict and prevent AD development and progression.

2017-11-30 | GSE107479 | GEO

Intake of high dairy products modifies the correlation between a-tocopherol levels and serum proteins related to lipid metabolism in subjects at risk of type 2 diabetes

Project description:The aim of this study is to investigate the relationship between a-tocopherol levels and serum protein profiles in human subjects at risk of T2D before and after intake of adequate dairy (AD) or high dairy (HD) products. In this crossover study, dietary intake of 25 subjects with hyperinsulinemia included: 1- pre-AD intake; 2- pre-HD intake; 3- post- AD intake (less or equal 2 servings/day); and 4- post-HD intake (more or equal than 4 servings/day) assessed by food frequency questionnaire. At each intake, serum a-tocopherol level was measured by gas chromatography-spectrometry and serum proteins were identified and quantified by liquid chromatography-mass spectrometry. Spearman correlation and gene ontology analyses were performed to identify biological pathways affected by dairy intake. a-tocopherol levels were associated with proteins that regulate lipid homeostasis and immune response. However, the increase intake of dairy products modified these associations in subjects with T2D.

2022-07-19 | MSV000089916 | MassIVE

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