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A functional variant of SMAD4 enhances macrophage recruitment and inflammatory response via TGF-? signal activation in Thoracic aortic aneurysm and dissection.

ABSTRACT: Thoracic aortic aneurysm and dissection (TAAD) is the most fatal macro vascular disease. The mortality of 48h after diagnosis of dissection is up to approximately 50-68%. However, the genetic factors and potential mechanism underlying sporadic TAAD remain largely unknown. Our previous study suggested rs12455792 variant of SMAD4 gene significantly contributed to the increased risk and might participated the pathological progression of TAAD. This investigation aims to test (1) the associations between rs12455792 and MØ recruitment, inflammatory response in aggressiveness of TAAD, and (2) the molecular mechanism accounting for their effects. In TGF-? signaling molecular detection, rs12455792 C>T variant activated the canonical and non-canonical TGF-? mediators. It also increased the secretion of chemotactic factors of HASMCs. To confirm the impact of this change, we detected MØ recruitment and infiltration in HASMCs and aortic tissues of TAAD patients. We found that MØ recruitment in cells and tissues with rs12455792 variant genotypes was increased than that in wild type groups. Moreover, rs12455792 variant increased M1 type inflammatory response, which might contribute much to TAAD progression. To mimic the SMAD4 suppression effect of rs12455792 in vivo, we constructed the SMAD4 KD mouse. After induction with Ang II for 4w, the thoracic aorta dilatation and vascular remodeling were more serious than that of wild type group. In conclusion, rs12455792 increased MØ recruitment, M1 type inflammatory response via activated TGF-? signaling, and further promoted vascular remodeling and pathological progress of TAAD.

SUBMITTER: Wang Y

PROVIDER: S-EPMC6326647 | biostudies-literature | 2018 Dec

REPOSITORIES: biostudies-literature

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A functional variant of <i>SMAD4</i> enhances macrophage recruitment and inflammatory response via TGF-β signal activation in Thoracic aortic aneurysm and dissection.

Wang Ying Y Yin Pei P Chen Yi-Huan YH Yu Yun-Sheng YS Ye Wen-Xue WX Huang Hao-Yue HY Ji Zhen-Chun ZC Shen Zhen-Ya ZY

Aging 20181201 12

Thoracic aortic aneurysm and dissection (TAAD) is the most fatal macro vascular disease. The mortality of 48h after diagnosis of dissection is up to approximately 50-68%. However, the genetic factors and potential mechanism underlying sporadic TAAD remain largely unknown. Our previous study suggested rs12455792 variant of <i>SMAD4</i> gene significantly contributed to the increased risk and might participated the pathological progression of TAAD. This investigation aims to test (1) the associati ...[more]

PMID: 30530919

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Project description:BackgroundThoracic aortic aneurysms progressively enlarge and predispose to acute aortic dissections. Up to 25% of individuals with thoracic aortic disease harbor an underlying Mendelian pathogenic variant. An evidence-based strategy for selection of genes to test in hereditary thoracic aortic aneurysm and dissection (HTAAD) helps inform family screening and intervention to prevent life-threatening thoracic aortic events.ObjectivesThe purpose of this study was to accurately identify genes that predispose to HTAAD using the Clinical Genome Resource (ClinGen) framework.MethodsWe applied the semiquantitative ClinGen framework to assess presumed gene-disease relationships between 53 candidate genes and HTAAD. Genes were classified as causative for HTAAD if they were associated with isolated thoracic aortic disease and were clinically actionable, triggering routine aortic surveillance, intervention, and family cascade screening. All gene-disease assertions were evaluated by a pre-defined curator-expert pair and subsequently discussed with an expert panel.ResultsGenes were classified based on the strength of association with HTAAD into 5 categories: definitive (n = 9), strong (n = 2), moderate (n = 4), limited (n = 15), and no reported evidence (n = 23). They were further categorized by severity of associated aortic disease and risk of progression. Eleven genes in the definitive and strong groups were designated as "HTAAD genes" (category A). Eight genes were classified as unlikely to be progressive (category B) and 4 as low risk (category C). The remaining genes were recent genes with an uncertain classification or genes with no evidence of association with HTAAD.ConclusionsThe ClinGen framework is useful to semiquantitatively assess the strength of gene-disease relationships for HTAAD. Gene categories resulting from the curation may inform clinical laboratories in the development, interpretation, and subsequent clinical implications of genetic testing for patients with aortic disease.

Dataset Information

A functional variant of SMAD4 enhances macrophage recruitment and inflammatory response via TGF-? signal activation in Thoracic aortic aneurysm and dissection.

Publications

A functional variant of <i>SMAD4</i> enhances macrophage recruitment and inflammatory response via TGF-β signal activation in Thoracic aortic aneurysm and dissection.

Similar Datasets

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