Abstract
Marfan syndrome (MFS) is a connective tissue disease caused by mutations in the FBN1 gene, 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 α-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 TGFβ 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.
Highlights
Marfan syndrome (MFS) is a connective tissue disorder caused by mutations in FBN1 gene encoding for the extracellular matrix (ECM) glycoprotein fibrillin-1, a structural component of 10–12-nm-sized calcium-binding microfibrils [1,2]
Aneurysmatic Aortopathy Is More Severe in MFS Patients
Increased α-SMA Expression Characterizes MFS-Derived Human Aortic Smooth Muscle Cells (HASMCs) but Not Human Adventitial Fibroblasts (HAFs) We investigated aortic smooth muscle cell (SMC) phenotypic differences in vitro
Summary
Marfan syndrome (MFS) is a connective tissue disorder caused by mutations in FBN1 gene encoding for the extracellular matrix (ECM) glycoprotein fibrillin-1, a structural component of 10–12-nm-sized calcium-binding microfibrils [1,2]. From the genetic phenotype, aneurysmatic aortic tissue in MFS and non-MFS patients shares common characteristics, such as elastic fiber and ECM degradation due to increased elastolysis and collagenolysis of the tunica media [9]. The latter occupies nearly 80% of the aortic wall and consists of layers of smooth muscle cells (SMCs) alternating with elastic laminae; collagen types I, III and IV; glycosaminoglycans (GAGs) and proteoglycans assembled in functional lamellar units [10,11]. Medial degeneration in MFS aortopathy is characterized by SMC loss and the accumulation of GAG-rich basophilic material [16]. Indication criteria for preventive aortic replacement are still insufficient; in this sense, biological parameters can help to overcome the current limitations of ultrasonography and magnetic resonance measurements [22]
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