Cyclophilin A/EMMPRIN Axis Is Involved in Pro-Fibrotic Processes Associated with Thoracic Aortic Aneurysm of Marfan Syndrome Patients

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.

Delicate regulation of IL-1β-mediated inflammation by cyclophilin A

“…It is well documented that CypA positively participates in cancer metastasis via type III EMT in colorectal cancer (Yamamoto et al, 2020) and lung cancer (Guo et al, 2018). In addition, CypA plays roles in tissue fibrosis, such as myocardial fibrosis (Seizer et al, 2012), thoracic aortic aneurysm fibrosis (Perrucci et al, 2020), and oral submucous fibrosis (Yuan et al, 2016). However, it is not clear whether CypA has an influence on type II EMT.…”

Paradoxical Changes: EMMPRIN Tissue and Plasma Levels in Marfan Syndrome-Related Thoracic Aortic Aneurysms

“…EMMPRIN is abundantly expressed in the cells and pathological tissues associated with TAAs [ 7 ]. Our study found that EMMPRIN levels were elevated in MFS TAA tissue, suggesting that, in MFS, the secretion of EMMPRIN is blocked, causing higher EMMPRIN abundance in the cells and tissue.…”

“…EMMPRIN is released into circulation through the secretion of extracellular vesicles and this process has been demonstrated to be dependent upon hydrolysis by the Membrane Type-1 MMP (MT1-MMP), also known as MMP-14 [ 3 , 4 ]. Both MT1-MMP and EMMPRIN are elevated in TAA tissue [ 5 , 6 , 7 ]. In other diseases, EMMPRIN abundance is often increased in both the pathological tissue and circulation [ 8 , 9 , 10 , 11 , 12 , 13 ].…”

Multi-omics in thoracic aortic aneurysm: the complex road to the simplification

“…Several other compounds provided, in the last years, promising results both in vivo and in vitro within MFS-TAA context [ 56 , 57 ]. Among worth of mention compounds, there are androgen inhibitors [ 58 ], folic acid [ 59 ], inhibitors of soluble guanylate cyclase [ 60 ], NAD [ 61 ], and apocynin [ 62 ], all displaying interesting in vivo outcomes by reducing TAA progression.…”