Research Paper Volume 10, Issue 12 pp 3683—3701
A functional variant of SMAD4 enhances macrophage recruitment and inflammatory response via TGF-β signal activation in Thoracic aortic aneurysm and dissection
- 1 Department of Cardiovascular Surgery of the First Affiliated Hospital and Institute for Cardiovascular Science, Soochow University, Suzhou, Jiangsu, China
- 2 Department of Thoracic Surgery, Taizhou People's Hospital, Taizhou, Jiangsu, China
received: August 6, 2018 ; accepted: November 15, 2018 ; published: December 7, 2018 ;https://doi.org/10.18632/aging.101662
How to Cite
Copyright: Wang et al. This is an open‐access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
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-β signaling molecular detection, rs12455792 C>T variant activated the canonical and non-canonical TGF-β 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-β signaling, and further promoted vascular remodeling and pathological progress of TAAD.
TAAD: thoracic aortic aneurysm and dissection; MØ: macrophage; TGF-β: transforming growth factor-β, GWAS: genome-wide association study; MALDI-TOF MS: matrix-assisted laser desorption ionization time-of-flight mass spectrometry; SNP: single nucleotide polymorphism; SMCs: smooth muscle cells; HASMCs: human aortic smooth muscle cells.