Piezo1 is required for outflow tract and aortic valve development

Autor: David Salgado, Guillaume Lebon, Amélie Pinard, Jean-Pierre Desvignes, Gaëlle Odelin, Adèle Faucherre, Jean François Avierinos, Hamid Moha Ou Maati, Alexis Theron, Stéphane Zaffran, Gwenaëlle Collod-Béroud, Nathalie Nasr, Chris Jopling
Přispěvatelé: Institut de Génomique Fonctionnelle (IGF), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Aix Marseille Université (AMU), Institut de génétique et microbiologie [Orsay] (IGM), Université Paris-Sud - Paris 11 (UP11)-Centre National de la Recherche Scientifique (CNRS), Génétique Médicale et Génomique Fonctionnelle (GMGF), Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Marseille medical genetics - Centre de génétique médicale de Marseille (MMG), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de cardiologie, Université de la Méditerranée - Aix-Marseille 2-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE), ANR-17-CE18-0001,AT2R-TRAAK-BIOANALGESICS,Caractérisations moléculaires et cellulaires de voies de signalisation de la douleur: contrôle de la douleur dans l'ulcère de buruli comme source d'inspiration pour la conception rationnelle de nouveaux analgésiques puissants(2017), Université de Montpellier (UM)-Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Montpellier 2 - Sciences et Techniques (UM2)-Centre National de la Recherche Scientifique (CNRS)
Jazyk: angličtina
Rok vydání: 2019
Předmět:
Models
Molecular
0301 basic medicine
Aortic valve
medicine.medical_specialty
Endothelium
Protein Conformation
Organogenesis
[SDV]Life Sciences [q-bio]
Fluorescent Antibody Technique
Gene Expression
030204 cardiovascular system & hematology
Ion Channels
03 medical and health sciences
0302 clinical medicine
Mechanosensitive ion channel
Bicuspid aortic valve
Genes
Reporter
Internal medicine
Animals
Humans
Ventricular outflow tract
Medicine
Amino Acid Sequence
Molecular Biology
Zebrafish
[SDV.BDD]Life Sciences [q-bio]/Development Biology
Alleles
030304 developmental biology
0303 health sciences
Cardiac cycle
biology
Heart development
business.industry
PIEZO1
Hemodynamics
Zebrafish Proteins
medicine.disease
biology.organism_classification
030104 developmental biology
medicine.anatomical_structure
Aortic Valve
Gene Knockdown Techniques
Mutation
Circulatory system
Cardiology
cardiovascular system
Cardiology and Cardiovascular Medicine
business
Zdroj: Journal of Molecular and Cellular Cardiology
Journal of Molecular and Cellular Cardiology, 2020, 143, pp.51-62. ⟨10.1016/j.yjmcc.2020.03.013⟩
Journal of Molecular and Cellular Cardiology, Elsevier, 2020, 143, pp.51-62. ⟨10.1016/j.yjmcc.2020.03.013⟩
ISSN: 0022-2828
1095-8584
Popis: Aims-During embryogenesis, the onset of circulatory blood flow generates a variety of hemodynamic forces which reciprocally induce changes in cardiovascular development and performance. It has been known for some time that these forces can be detected by as yet unknown mechanosensory systems which in turn promote cardiogenic events such as outflow tract and aortic valve development. PIEZO1 is a mechanosensitive ion channel present in endothelial cells where it serves to detect hemodynamic forces making it an ideal candidate to play a role during cardiac development. We sought to determine whether PIEZO1 is required for outflow tract and aortic valve development.Methods and results-By analysing heart development in zebrafish we have determined thatpiezo1is expressed in the developing outflow tract where it serves to detect hemodynamic forces. In particular, we have found that mechanical forces generated during the cardiac cycle activate Piezo1 which triggers nitric oxide to be released in the outflow tract. Consequently, disrupting Piezo1 signalling leads to defective outflow tract and aortic valve development and indicates this gene may be involved in the etiology of congenital heart diseases. Based on these findings, we analysed genomic data generated from a cohort of bicuspid aortic valve patients and identified 3 probands who each harboured a novel variant inPIEZO1. Subsequentin vitroandin vivoassays indicates that these variants behave as dominant negatives leading to an inhibition of normal PIEZO1 mechanosensory activity and defective aortic valve development.Conclusion-These data indicate that the mechanosensitive ion channelpiezo1is required for OFT and aortic valve development and, furthermore, dominant negative variants ofPIEZO1appear to be associated with BAV in humans.
Databáze: OpenAIRE
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