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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

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

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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).

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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.

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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.

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