Genetic Deletion of Socs3 in Smooth Muscle Cells Ameliorates Aortic Dissection in Mice
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PROVIDER: PRJNA612890 | ENA |
REPOSITORIES: ENA
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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
Project description:The heterogeneity of smooth muscle cells in aortic dissection was determined by single-cell sequencing
2022-05-30 | GSE203594 | GEO
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
Project description:The role of macrophage Socs3 in the pathogenesis of aortic dissection
| PRJNA420217 | ENA
Project description:Smooth muscle cell TGFβ signaling is one of the primary drivers of smooth muscle cell maturation. Inhibition of smooth muscle cell TGFβ signaling in hyperlipidemic mice induces vessel wall inflammation and vessel wall dilation/dissection and leads aortic aneurysm. We performed bulk RNAseq method to examine smooth muscle cell gene expression profile using fresh human tissues from normal aortic media smooth muscle cells and aneurysm aortic media smooth muscle cells.
2020-03-01 | GSE140947 | GEO
Project description:Smooth muscle cell TGFβ signaling is one of the primary drivers of smooth muscle cell maturation. Inhibition of smooth muscle cell TGFβ signaling in hyperlipidemic mice induces vessel wall inflammation and vessel wall dilation/dissection and leads aortic aneurysm. We performed scRNAseq method to examine smooth muscle cell gene expression profile using Apoe and SMC specific TGFbR2 KO in Apoe background mice.
2020-03-01 | GSE141031 | GEO
Project description:Aortic dissection (AD) is the acute destruction of aortic wall and is reportedly induced by inflammatory response. Here we investigated the role of smooth muscle Socs3 (a negative regulator of Janus kinases/signal transducer and activator of transcription signaling) in AD pathogenesis using a mouse model generated via β-aminopropionitrile and angiotensin II infusion. Socs3 deletion specifically in smooth muscle cells yielded a chronic inflammatory response of the aortic wall, which was associated with increased fibroblasts, reinforced aortic tensile strength, and less-severe tissue destruction. Although an acute inflammatory response is detrimental in AD, smooth muscle-regulated inflammatory response seemed protective against AD.
| S-EPMC7046542 | 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: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:and with higher incidence if associated to bicuspid aortic valve (BAV) for unknown reasons. TAA is usually diagnosed fortuitously and the lack of effective drug therapy to delay progression and avoid dissection lies in the limited knowledge of pathophysiology. Objectives. We aimed to identify the molecular hallmarks that difference the aortic dilatation associated to bicuspid (BAV) and tricuspid aortic valve (TAV) patients while setting plasma diagnostic molecular panels valve-associated. Methods. Sporadic TAA patients and control subjects (n=91) were classified according to valve type (BAV, TAV). Vascular smooth muscle cells isolated from TAA patients’ aortas were firstly analyzed by mass spectrometry based high-throughput proteomics according to valve type. Extracellularly secreted proteins were secondly analyzed in plasma from TAA patients versus control subjects as diagnostic candidates. Results. Aneurysmal aortas from BAV patients showed a stress phenotype, weakened extracellular matrix interactions, DNA damage and affected protein homeostasis compared to TAV patients. Two plasma marker panels of sporadic TAA valveassociated were identified, showing significant correlation with aortic diameter for C1QTNF5, LAMA2, and SPARC proteins, in BAV patients, and for CP and FAP proteins, in TAV patients. Conclusions. The arterial wall of BAV patients shows a limited capacity to counteract drivers of sporadic TAA while resembling aged arteries.The molecular pathways identified here support the need of differential molecular diagnosis and therapeutic approaches for BAV and TAV patients.
2024-10-17 | PXD043062 | Pride