| Title: |
Multimodality imaging and transcriptomics to phenotype mitral valve dystrophy in a unique knock-in Filamin-A rat model |
| Authors: |
Delwarde, Constance; Toquet, Claire; Aumond, Pascal; Kayvanjoo, Amir Hossein; Foucal, Adrien; Le Vely, Benjamin; Baudic, Manon; Lauzier, Benjamin; Blandin, Stéphanie; Véziers, Joëlle; Paul-Gilloteaux, Perrine; Lecointe, Simon; Baron, Estelle; Massaiu, Ilaria; Poggio, Paolo; Rémy, Séverine; Anegon, Ignacio; Le Marec, Hervé; Monassier, Laurent; Schott, Jean-Jacques; Mass, Elvira; Barc, Julien; Le Tourneau, Thierry; Merot, Jean |
| Contributors: |
ITX-lab unité de recherche de l'institut du thorax UMR1087 UMR6291 (ITX-lab); Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Nantes Université - UFR de Médecine et des Techniques Médicales (Nantes Univ - UFR MEDECINE); Nantes Université - pôle Santé; Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ)-Nantes Université - pôle Santé; Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ); Universität Bonn = University of Bonn; Structure fédérative de recherche François Bonamy (Nantes Univ - SFR François Bonamy); Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Nantes Université - pôle Santé; Regenerative Medicine and Skeleton (RMeS); École nationale vétérinaire, agroalimentaire et de l'alimentation Nantes-Atlantique (ONIRIS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Nantes Université - UFR Odontologie (Nantes Univ – UFR Odonto); Centre de Recherche en Transplantation et Immunologie - Center for Research in Transplantation and Translational Immunology (U1064 Inserm - CR2TI); Institut National de la Santé et de la Recherche Médicale (INSERM)-Nantes Université - UFR de Médecine et des Techniques Médicales (Nantes Univ - UFR MEDECINE); Laboratoire de pharmacologie et toxicologie neurocardiovasculaire (LPTNC); Université de Strasbourg (UNISTRA); ANR-18-CE45-0015,CROCOVAL,Recalage transmodal en microscopies corrélatives pour la caractérisation physiopathologique de la valvulopathie(2018); ANR-10-INBS-0004,France-BioImaging,Développment d'une infrastructure française distribuée coordonnée(2010) |
| Source: |
ISSN: 0008-6363 ; Cardiovascular Research ; https://hal.science/hal-03765601 ; Cardiovascular Research, 2023, 119 (3), pp.759-771. ⟨10.1093/cvr/cvac136⟩. |
| Publisher Information: |
CCSD; Oxford University Press (OUP) |
| Publication Year: |
2023 |
| Collection: |
Université de Nantes: HAL-UNIV-NANTES |
| Subject Terms: |
[SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system; [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry; Molecular Biology/Genomics [q-bio.GN] |
| Description: |
International audience ; Aims Degenerative mitral valve dystrophy (MVD) leading to mitral valve prolapse is the most frequent form of MV disease, and there is currently no pharmacological treatment available. The limited understanding of the pathophysiological mechanisms leading to MVD limits our ability to identify therapeutic targets. This study aimed to reveal the main pathophysiological pathways involved in MVD via the multimodality imaging and transcriptomic analysis of the new and unique Knock-In (KI) rat model for the FlnA-P637Q mutation associated-MVD.Methods and Results WT and KI rats were evaluated morphologically, functionally, and histologically between 3-week-old and 3-to-6-month-old based on Doppler echocardiography, 3D micro-computed tomography (microCT), and standard histology. RNA-sequencing and Assay for Transposase-Accessible Chromatin (ATAC-seq) were performed on 3-week-old WT and KI mitral valves and valvular cells, respectively, to highlight the main signaling pathways associated with MVD. Echocardiographic exploration confirmed MV elongation (2.0 ± 0.1 mm versus 1.8 ± 0.1, p = 0.001), as well as MV thickening and prolapse in KI animals compared to WT at 3 weeks. 3D MV volume quantified by microCT was significantly increased in KI animals (+58% versus WT, p = 0.02). Histological analyses revealed a myxomatous remodeling in KI MV characterized by proteoglycans accumulation. A persistent phenotype was observed in adult KI rats. Signaling pathways related to extracellular matrix homeostasis, response to molecular stress, epithelial cell migration, endothelial to mesenchymal transition, chemotaxis and immune cell migration, were identified based on RNA-seq analysis. ATAC-seq analysis points to the critical role of TGF-β and inflammation in the disease.Conclusion The KI FlnA-P637Q rat model mimics human myxomatous mitral valve dystrophy, offering a unique opportunity to decipher pathophysiological mechanisms related to this disease. Extracellular matrix organization, epithelial cell migration, ... |
| Document Type: |
article in journal/newspaper |
| Language: |
English |
| DOI: |
10.1093/cvr/cvac136 |
| Availability: |
https://hal.science/hal-03765601; https://hal.science/hal-03765601v1/document; https://hal.science/hal-03765601v1/file/2022-06-21_Paper-FLNA-AuthorCopy.pdf; https://doi.org/10.1093/cvr/cvac136 |
| Rights: |
https://about.hal.science/hal-authorisation-v1/ ; info:eu-repo/semantics/OpenAccess |
| Accession Number: |
edsbas.FF67EC6D |
| Database: |
BASE |