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

Zhen-Ya Shen,Yun-Sheng Yu,Ying Wang,Pei Yin,Wen-Xue Ye,Hao-Yue Huang,Zhen-Chun Ji,Yi-Huan Chen

doi:10.18632/aging.101662

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-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.

Highlights

Aortic aneurysm and dissection is the most fatal macro vascular disease, accounting for over 152,000 new deaths in the United States per annum [1]
The functional single nucleotide polymorphism (SNP) rs12455792 C>T variant was correlated with increased aortic diameter of thoracic aortic aneurysm and dissection (TAAD) patients (r=0.164, P=0.020, positive correlation in screening data), yielding the most significant results (Supplementary Table 3). rs12455792 was bioinformatical predicted as a proximal transcription regulatory loci, i.e. it was a functional SNP
Since we have proved that rs12455792 variant suppressed SMAD4 expression, siRNA-SMAD4 were transfected into human aortic smooth muscle cells (HASMCs) to mimic the impact of rs12455792 variant genotype

Summary

Introduction

Aortic aneurysm and dissection is the most fatal macro vascular disease, accounting for over 152,000 new deaths in the United States per annum [1]. Related studies have shown that the pathological mechanism of thoracic aortic aneurysm and dissection (TAAD) involves macrophages (MØ) recruitment, inflammatory reactions and vascular remodeling [2]. MØ is a pivotal mediator involved in vascular remodeling and aneurysm dissection and rupture [3]. Increasing evidences revealed that MØ presented anti-inflammatory effects via secreting proinflammatory factors and chemokines in vascular injury region, initiated wound-healing and tissue remodeling [4]. MØ acquires distinct functional phenotypes via different polarization www.aging‐us.com phenotypes-M1 or M2. The imbalance between M1 and M2 type MØ accelerated the progression or rupture of aortic aneurysms [3]

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Discussion

Conclusion