RNA sequencing-based transcriptome profiling of cardiac tissue implicates novel putative disease mechanisms in FLNC-associated arrhythmogenic cardiomyopathy.

Fecha de publicación: 01/03/2020 Fecha Ahead of Print: 06/12/2019

Autores de IIS La Fe

Participantes ajenos a IIS La Fe

Hall CL
Gurha P
Sabater-Molina M
Asimaki A
Futema M
Lovering RC
Suárez MP
Aguilera B
Coarfa C
Robertson MJ
Cheedipudi SM
Ng KE
Delaney P
Hernández JP
Pastor F
McKenna WJ
Marian AJ
Syrris P

Grupos

Cardiopatías familiares, muerte súbita y mecanismos de enfermedad (CAFAMUSME)

Investigador Principal

Aitana Braza Boils
Medicina Intensiva

Leader

Álvaro Castellanos Ortega

Abstract

Arrhythmogenic cardiomyopathy (ACM) encompasses a group of inherited cardiomyopathies including arrhythmogenic right ventricular cardiomyopathy (ARVC) whose molecular disease mechanism is associated with dysregulation of the canonical WNT signalling pathway. Recent evidence indicates that ARVC and ACM caused by pathogenic variants in the FLNC gene encoding filamin C, a major cardiac structural protein, may have different molecular mechanisms of pathogenesis. We sought to identify dysregulated biological pathways in FLNC-associated ACM. RNA was extracted from seven paraffin-embedded left ventricular tissue samples from deceased ACM patients carrying FLNC variants and sequenced. Transcript levels of 623 genes were upregulated and 486 genes were reduced in ACM in comparison to control samples. The cell adhesion pathway and ILK signalling were among the prominent dysregulated pathways in ACM. Consistent with these findings, transcript levels of cell adhesion genes JAM2, NEO1, VCAM1 and PTPRC were upregulated in ACM samples. Moreover, several actin-associated genes, including FLNC, VCL, PARVB and MYL7, were suppressed, suggesting dysregulation of the actin cytoskeleton. Analysis of the transcriptome for dysregulated biological pathways predicted activation of inflammation and apoptosis and suppression of oxidative phosphorylation and MTORC1 signalling in ACM. Our data suggests dysregulated cell adhesion and ILK signalling as novel putative pathogenic mechanisms of ACM caused by FLNC variants which are distinct from the postulated disease mechanism of classic ARVC caused by desmosomal gene mutations. This knowledge could help in the design of future gene therapy strategies which would target specific components of these pathways and potentially lead to novel treatments for ACM.

Datos de la publicación

ISSN/ISSNe:: 0167-5273, 1874-1754
Tipo:: Article
Páginas:: 124-130
DOI:: 10.1016/j.ijcard.2019.12.002
Factor de Impacto:: 1,406 SCImago ℠
Cuartil:: Q1 SCImago ℠

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Métricas

Filiaciones

Hall CL:: Centre for Heart Muscle Disease, Institute of Cardiovascular Science, University College London, London, UK
Gurha P:: Center for Cardiovascular Genetics, Institute of Molecular Medicine, University of Texas Health Sciences Center at Houston, USA
Sabater-Molina M:: Laboratorio de Cardiogenética, Instituto Murciano de Investigación Biosanitaria and Universidad de Murcia, Murcia, Spain
Asimaki A:: Cardiology Clinical Academic Group, Molecular and Clinical Sciences Research Institute, St Georges University of London, London, UK
Futema M:: Centre for Heart Muscle Disease, Institute of Cardiovascular Science, University College London, London, UK
Lovering RC:: Functional Gene Annotation Group, Pre-clinical and Fundamental Science, Institute of Cardiovascular Science, University College London, London, UK
Suárez MP:: Instituto Nacional de Toxicologia y Ciencias Forenses de Madrid (INTCF), Madrid, Spain
Aguilera B:: Instituto Nacional de Toxicologia y Ciencias Forenses de Madrid (INTCF), Madrid, Spain
Molina P:: Instituto de Investigación. Department of Pathology at the Instituto de Medicina Legal y Ciencias Forenses de Valencia (IMLCF-Valencia), Histology Unit at the Universitat de València, and Research Group on Inherited Heart Diseases, Sudden Death and Mechanisms of Disease (CaFaMuSMe) from the Instituto de Investigación Sanitaria (IIS) La Fe, Valencia, Spain
Zorio E:: Instituto de Investigación. Cardiology Department at Hospital Universitario y Politécnico La Fe and Research Group on Inherited Heart Diseases, Sudden Death and Mechanisms of Disease (CaFaMuSMe) from the Instituto de Investigación Sanitaria (IIS) La Fe, Valencia, Spain

Center for Biomedical Network Research on Cardiovascular Diseases (CIBERCV), Madrid, Spain
Coarfa C:: Baylor College of Medicine, Houston, TX, USA
Robertson MJ:: Baylor College of Medicine, Houston, TX, USA
Cheedipudi SM:: Center for Cardiovascular Genetics, Institute of Molecular Medicine, University of Texas Health Sciences Center at Houston, USA
Ng KE:: William Harvey Heart Centre, Queen Mary University of London, London, UK
Delaney P:: William Harvey Heart Centre, Queen Mary University of London, London, UK
Hernández JP:: Instituto de Medicina Legal de Murcia (IML-Murcia), Murcia, Spain
Pastor F:: Servicio de Anatomía Patológica del Hospital Reina Sofía, Murcia, Spain
Gimeno JR:: Servicio de Cardiologia del Hospital Universitario Virgen de la Arrixaca and Departamento de Medicina Interna de la Universidad de Murcia, Murcia, Spain

Center for Biomedical Network Research on Cardiovascular Diseases (CIBERCV), Madrid, Spain
McKenna WJ:: Centre for Heart Muscle Disease, Institute of Cardiovascular Science, University College London, London, UK
Marian AJ:: Center for Cardiovascular Genetics, Institute of Molecular Medicine, University of Texas Health Sciences Center at Houston, USA
Syrris P:: Centre for Heart Muscle Disease, Institute of Cardiovascular Science, University College London, London, UK

Keywords

Arrhythmogenic cardiomyopathy, Filamin C, Focal adhesion pathway, Integrin linked kinase pathway, RNA sequencing

Campos de estudio

Proyectos asociados

RED INVESTIGACION (RECAVA)

RD06/0014/0004 . INSTITUTO DE SALUD CARLOS III; FUNDACION PARA LA INV BIOMEDICA- HOSPITAL GREGORIO MARAÑON; FUNDACIÓN PARA LA INVESTIGACIÓN DEL HOSPITAL UNIVERSITARIO LA FE DE LA COMUNIDAD VALENCIANA . 2006