Specific miRNA and Gene Deregulation Characterize the Increased Angiogenic Remodeling of Thoracic Aneurysmatic Aortopathy in Marfan Syndrome

被引：18

作者：

D'Amico, Federico ^{[1
]}

Doldo, Elena ^{[1
]}

Pisano, Calogera ^{[2
]}

Scioli, Maria Giovanna ^{[1
]}

Centofanti, Federica ^{[1
]}

Proietti, Giulia ^{[1
]}

Falconi, Mattia ^{[3
]}

Sangiuolo, Federica ^{[4
]}

Ferlosio, Amedeo ^{[1
]}

Ruvolo, Giovanni ^{[2
]}

Orlandi, Augusto ^{[1
]}

机构：

[1] Univ Roma Tor Vergata, Dept Biomed & Prevent, Anat Pathol, Via Montpellier 1, I-00133 Rome, Italy

[2] Univ Roma Tor Vergata, Dept Expt Med & Surg, Cardiac Surg, I-00133 Rome, Italy

[3] Univ Roma Tor Vergata, Dept Biol, I-00133 Rome, Italy

[4] Univ Roma Tor Vergata, Dept Biomed & Prevent, Med Genet, I-00133 Rome, Italy

来源：

INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES | 2020年 / 21卷 / 18期

关键词：

Marfan syndrome; thoracic aortic aneurysm; fibrillin-1; aortic smooth muscle cells; SMOOTH-MUSCLE-CELLS; PHENOTYPIC HETEROGENEITY INFLUENCES; ENDOTHELIAL PROGENITOR CELLS; EXTRACELLULAR-MATRIX; AORTIC-ANEURYSM; IN-VITRO; EXPRESSION; ATHEROSCLEROSIS; PROLIFERATION; MODULATION;

D O I：

10.3390/ijms21186886

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Marfan syndrome (MFS) is a connective tissue disease caused by mutations in theFBN1gene, leading to alterations in the extracellular matrix microfibril assembly and the early formation of thoracic aorta aneurysms (TAAs). Non-genetic TAAs share many clinico-pathological aspects with MFS and deregulation of some microRNAs (miRNAs) has been demonstrated to be involved in the progression of TAA. In this study, 40 patients undergoing elective ascending aorta surgery were enrolled to compare TAA histomorphological features, miRNA profile and related target genes in order to find specific alterations that may explain the earlier and more severe clinical outcomes in MFS patients. Histomorphological, ultrastructural and in vitro studies were performed in order to compare aortic wall features of MFS and non-MFS TAA. MFS displayed greater glycosaminoglycan accumulation and loss/fragmentation of elastic fibers compared to non-MFS TAA. Immunohistochemistry revealed increased CD133(+)angiogenic remodeling, greater MMP-2 expression, inflammation and smooth muscle cell (SMC) turnover in MFS TAA. Cultured SMCs from MFS confirmed higher turnover and alpha-smooth muscle actin expression compared with non-MFS TAA. Moreover, twenty-five miRNAs, including miR-26a, miR-29, miR-143 and miR-145, were found to be downregulated and only miR-632 was upregulated in MFS TAA in vivo. Bioinformatics analysis revealed that some deregulated miRNAs in MFS TAA are implicated in cell proliferation, extracellular matrix structure/function and TGF beta signaling. Finally, gene analysis showed 28 upregulated and seven downregulated genes in MFS TAA, some of them belonging to the CDH1/APC and CCNA2/TP53 signaling pathways. Specific miRNA and gene deregulation characterized the aortopathy of MFS and this was associated with increased angiogenic remodeling, likely favoring the early and more severe clinical outcomes, compared to non-MFS TAA. Our findings provide new insights concerning the pathogenetic mechanisms of MFS TAA; further investigation is needed to confirm if these newly identified specific deregulated miRNAs may represent potential therapeutic targets to counteract the rapid progression of MFS aortopathy.

引用

页码：1 / 20

页数：20