Abstract
Background: Marfan syndrome (MFS) is a genetic disease, characterized by thoracic aortic aneurysm (TAA), which treatment is to date purely surgical. Understanding of novel molecular targets is mandatory to unveil effective pharmacological approaches. Cyclophilin A (CyPA) and its receptor EMMPRIN are associated with several cardiovascular diseases, including abdominal aortic aneurysm. Here, we envisioned the contribution of CyPA/EMMPRIN axis in MFS-related TAA. Methods: We obtained thoracic aortic samples from healthy controls (HC) and MFS patients’ aortas and then isolated vascular smooth muscle cells (VSMC) from the aortic wall. Results: our findings revealed that MFS aortic tissue samples isolated from the dilated zone of aorta showed higher expression levels of EMMPRIN vs. MFS non-dilated aorta and HC. Interestingly, angiotensin II significantly stimulated CyPA secretion in MFS-derived VSMC (MFS-VSMC). CyPA treatment on MFS-VSMC led to increased levels of EMMPRIN and other MFS-associated pro-fibrotic mediators, such as TGF-β1 and collagen I. These molecules were downregulated by in vitro treatment with CyPA inhibitor MM284. Our results suggest that CyPA/EMMPRIN axis is involved in MFS-related TAA development, since EMMPRIN is upregulated in the dilated zone of MFS patients’ TAA and the inhibition of its ligand, CyPA, downregulated EMMPRIN and MFS-related markers in MFS-VSMC. Conclusions: these insights suggest both a novel detrimental role for CyPA/EMMPRIN axis and its inhibition as a potential therapeutic strategy for MFS-related TAA treatment.
Highlights
Marfan syndrome (MFS) is a connective tissue disease with an autosomal dominant inheritance and an estimated incidence of 1:5000 individuals [1]
RNA extracts from the ascending aortic tissues. qRT-PCR analyses showed an upregulation of genes encoding several pro-fibrotic factors, such as collagen I (COL1A1) and connective tissue growth factor (CTGF) in aortic MFS patients’ samples vs. healthy controls (HC) (Figure 1a)
Similar results were obtained for SMTN, a gene encoding the typical vascular smooth muscle cells (VSMC) marker smoothelin, and genes related to TGF-β1, such as TGFB1 itself, type 1 transforming growth factor-β (TGF-β) receptor (TGFBR1), and latent TGF-β binding protein 1 (LTBP1)
Summary
Marfan syndrome (MFS) is a connective tissue disease with an autosomal dominant inheritance and an estimated incidence of 1:5000 individuals [1] This disorder is caused by mutations in the FBN1 gene encoding fibrillin-1, an extracellular matrix (ECM) protein that provides elasticity and structural support to several tissues [2]. FBN1 mutations lead to impaired fibrillin-1 protein synthesis, secretion and/or incorporation in ECM, determining a microfibrillar architecture degeneration and destruction of the ECM integrity [4]. As a consequence, this genetic defect leads to pleiotropic manifestations, such as skeletal overgrowth, ocular lens luxation (i.e., ectopia lentis), and cardiovascular events as the progressive aortic-root dilation [5].
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