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Open AccessArticle

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

1
Unità di Medicina Rigenerativa e Biologia Vascolare, Centro Cardiologico Monzino-IRCCS, 20138 Milan, Italy
2
Centro Malattie Rare, Marfan Clinic, U.O. Cardiologia, ASST FBF-Sacco, 20157 Milan, Italy
3
Centro di Cardiogenetica Vascolare, IRCCS Policlinico San Donato, San Donato Milanese, 20097 Milan, Italy
4
Consiglio Nazionale delle Ricerche (CNR), Istituto di Ricerca e di Innovazione Biomedica (IRIB), 90146 Palermo, Italy
5
Dipartimento di Scienze Biomediche e Cliniche “L. Sacco”, Università degli Studi, 20157 Milan, Italy
6
Departament Biomedicina, Universitat de Barcelona and Institut d’Investigacions Mèdiques August Pi i Sunyer (IDIBAPS), 08036 Barcelona, Spain
7
Max-Planck Institute for Biophysical Chemistry, 37077 Göttingen, Germany
8
Enzymology department, Institute of Biochemistry and Biotechnology, Martin-Luther-University Halle-Wittenberg, 06120 Halle, Germany
9
Unità Operativa di Chirurgia Cardiaca, Centro Cardiologico Monzino IRCCS, 20138 Milan, Italy
10
Dipartimento di Scienze Cliniche e di Comunità, Università degli Studi, 20122 Milan, Italy
11
Treviso Tissue Bank Foundation, 31100 Treviso, Italy
12
Dipartimento di Chirurgia Cardiovascolare, Centro Cardiologico Monzino IRCCS, 20138 Milan, Italy
*
Author to whom correspondence should be addressed.
Equal contribution as last authors.
Cells 2020, 9(1), 154; https://doi.org/10.3390/cells9010154
Received: 4 November 2019 / Revised: 16 December 2019 / Accepted: 3 January 2020 / Published: 8 January 2020
(This article belongs to the Section Cellular Pathology)
: 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.
Keywords: thoracic aortic aneurysm; EMMPRIN; fibrosis; vascular smooth muscle cells; Cyclophilin A thoracic aortic aneurysm; EMMPRIN; fibrosis; vascular smooth muscle cells; Cyclophilin A
MDPI and ACS Style

Perrucci, G.L.; Rurali, E.; Corlianò, M.; Balzo, M.; Piccoli, M.; Moschetta, D.; Pini, A.; Gaetano, R.; Antona, C.; Egea, G.; Fischer, G.; Malešević, M.; Alamanni, F.; Cogliati, E.; Paolin, A.; Pompilio, G.; Nigro, P. Cyclophilin A/EMMPRIN Axis Is Involved in Pro-Fibrotic Processes Associated with Thoracic Aortic Aneurysm of Marfan Syndrome Patients. Cells 2020, 9, 154.

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