The role of macrophage Socs3 in the pathogenesis of aortic dissection
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PROVIDER: PRJNA420217 | ENA |
REPOSITORIES: ENA
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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: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:BackgroundAortic dissection (AD) is a life-threatening medical emergency caused by the abrupt destruction of the intimomedial layer of the aortic walls. Given that previous studies have reported the involvement of proinflammatory cytokine interleukin-6 in AD pathogenesis, we investigated the role of signal transduction and activator of transcription 3 signaling, a downstream pathway of interleukin-6 in macrophages in pathogenesis of AD.Methods and resultsWe characterized the pathological and molecular events triggered by aortic stress, which can lead to AD. Aortic stress on the suprarenal aorta because of 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 healed 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 smooth muscle cells and transforming growth factor beta signaling, which are likely to participate in tissue repair. Human AD samples revealed signal transduction and activator of transcription 3 activation in adventitial macrophages adjacent to the site of tissue destruction.ConclusionsThese 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.
| S-EPMC5850160 | biostudies-literature
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
Project description:Genetic Deletion of Socs3 in Smooth Muscle Cells Ameliorates Aortic Dissection in Mice
| PRJNA612890 | ENA
Project description:To screen serum molecular markers systematically amid aortic dissection and acute coronary syndrome, preliminary identify the pathogenesis of acute aortic dissection.
2022-03-25 | PXD032857 |
Project description:Single-Cell RNA-Seq Analysis Reveals Macrophage Involved in Pathogenesis of Human sporadic type A aortic dissection
| PRJNA882355 | ENA
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:Macrophages play an important role in the progression of sporadic acute type A aortic dissection (ATAAD). The aim of this study was to characterize the cellular heterogeneity of macrophages in AD tissues by scRNA-seq. Ascending aortic wall tissue from 6 ATAAD patients and 3 heart transplant donors were assessed by scRNA-seq, then analyzed and validated by various bioinformatics algo-rithms and histopathology experiments. The results revealed the proportion of macrophages in AD tissues (24.51%) was significantly higher than that in normal tissues (13.69%). Among the 6 macro-phage subclusters, pro-inflammatory macrophages accounted for 14.96% in the AD group, and 0.18% in the normal group. Chemokine and inflammation related genes (CCL2, CCL20, S100A8, and S100A9) were expressed more intensively in macrophages in AD tissue than that in the normal tissues. Ad-ditionally, intercellular communication analysis and transcription factor analysis indicated activation of inflammation and degradation of the extracellular matrix in AD tissues. Finally, immunohisto-chemistry, immunofluorescence and western blot experiments confirmed the overexpression of macrophage marker genes (CD68 and CD163) and matrix metalloproteinases (MMP9 and MMP2) in AD tissues. Collectively, our study provides a preliminary evaluation of the role of macrophages in AD and potentially aid in the development of therapeutic options in the future.
2022-09-23 | GSE213740 | 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