Centro Cardiologico Monzino IRCCS
Published January 8, 2020 | Version v1
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Cyclophilin A/EMMPRIN Axis Is Involved in Pro-Fibrotic Processes Associated with Thoracic Aortic Aneurysm of Marfan Syndrome Patients

Authors/Creators

  • 1. Centro Cardiologico Monzino-IRRCS
  • 2. Centro Malattie Rare, Marfan Clinic, U.O. Cardiologia, ASST FBF-Sacco, 20157 Milan, Italy
  • 3. Consiglio Nazionale delle Ricerche (CNR), Istituto di Ricerca e di Innovazione Biomedica (IRIB), 90146 Palermo, Italy
  • 4. Dipartimento di Scienze Biomediche e Cliniche "L. Sacco", Università degli Studi, 20157 Milan, Italy
  • 5. Departament Biomedicina, Universitat de Barcelona and Institut d'Investigacions Mèdiques August Pi i Sunyer (IDIBAPS), 08036 Barcelona, Spain
  • 6. Max-Planck Institute for Biophysical Chemistry, 37077 Göttingen, Germany
  • 7. Enzymology department, Institute of Biochemistry and Biotechnology, Martin-Luther-University Halle-Wittenberg, 06120 Halle, Germany
  • 8. Unità Operativa di Chirurgia Cardiaca, Centro Cardiologico Monzino IRCCS, 20138 Milan, Italy
  • 9. Treviso Tissue Bank Foundation, 31100 Treviso, Italy

Description

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.

Notes

Ministry of Health funds (Ricerca Corrente RC2015-2018

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Additional details

Related works

Is derived from
Journal article: 10.3390/cells9010154 (DOI)