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Your search keyword '"Zeina R. Al Sayed"' showing total 4 results
Start Over Author "Zeina R. Al Sayed" Topic 030304 developmental biology
4 results on '"Zeina R. Al Sayed"'

1. Human model of IRX5 mutations reveals key role for this transcription factor in ventricular conduction

Author

Bastien Cimarosti, Guillaume Lamirault, Hanan Hamamy, Nathalie Gaborit, Céline Marionneau, Flavien Charpentier, Gildas Loussouarn, Laurent David, Kazem Zibara, Nicolas Jacob, Virginie Forest, Mariam Jouni, Caroline Chariau, Carine Bonnard, Hülya Kayserili, Bruno Reversade, Anne Gaignerie, Jean-Baptiste Gourraud, Robin Canac, Zeina R Al Sayed, Patricia Lemarchand, Aurore Girardeau, Karabey, Hülya Kayserili (ORCID 0000-0003-0376-499X & YÖK ID 7945), Reversade, Bruno, Al Sayed, Zeina R, Canac, Robin, Cimarosti, Bastien, Bonnard, Carine, Gourraud, Jean-Baptiste, Hamamy, Hanan, Girardeau, Aurore, Jouni, Mariam, Jacob, Nicolas, Gaignerie, Anne, Chariau, Caroline, David, Laurent, Forest, Virginie, Marionneau, Céline, Charpentier, Flavien, Loussouarn, Gildas, Lamirault, Guillaume, Zibara, Kazem, Lemarchand, Patricia, Gaborit, Nathalie, School of Medicine, unité de recherche de l'institut du thorax UMR1087 UMR6291 (ITX), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), Agency for science, technology and research [Singapore] (A*STAR), Department of Genetic Medicine and Development [Geneva], Université de Genève (UNIGE), Koç University, Structure fédérative de recherche François Bonamy (SFR François Bonamy), Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche en Santé de l'Université de Nantes (IRS-UN), Centre de Recherche en Transplantation et Immunologie (U1064 Inserm - CRTI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Institut de transplantation urologie-néphrologie (ITUN), Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes), National University of Singapore (NUS), University of Amsterdam [Amsterdam] (UvA), Laboratory of Stem Cells [Lebanese, Beirut] (ER045-PRASE), Lebanese University [Beirut] (LU), This work was funded by grants from The National Research Agency [HEART iPS ANR-15-CE14-0019-01], and La Fédération Française de Cardiologie. Nathalie Gaborit was laureate of fellowships from Fondation Lefoulon-Delalande and International Incoming Fellowship FP7-PEOPLE-2012-IIF [PIIF-GA-2012-331436]. Zeina R. Al Sayed is supported by Eiffel scholarship program of Excellence (Campus France), by Doctoral School of Science and Technology-Lebanese University and The Fondation Genavie., ACS - Heart failure & arrhythmias, ARD - Amsterdam Reproduction and Development, Unité de recherche de l'institut du thorax (ITX-lab), and Université de Genève = University of Geneva (UNIGE)

Subjects
conduction, IRX5 mutations, Physiology, Transcription factor complex, Connexin, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, 030204 cardiovascular system & hematology, Biology, arrhythmia, Ventricular action potential, 03 medical and health sciences, 0302 clinical medicine, Physiology (medical), transcription factors, Cardiac conduction, Transcription factor, [SDV.BC] Life Sciences [q-bio]/Cellular Biology, 030304 developmental biology, 0303 health sciences, GATA4, Sodium channel, Depolarization, Human-induced pluripotent stem cells, Cell biology, human induced pluripotent stem cells, cardiovascular system, IRX5, Cardiology and Cardiovascular Medicine, Hamamy syndrome
Abstract

Aims: several inherited arrhythmic diseases have been linked to single gene mutations in cardiac ion channels and interacting proteins. However, the mechanisms underlying most arrhythmias, are thought to involve altered regulation of the expression of multiple effectors. In this study, we aimed to examine the role of a transcription factor (TF) belonging to the Iroquois homeobox family, IRX5, in cardiac electrical function. Methods and results: using human cardiac tissues, transcriptomic correlative analyses between IRX5 and genes involved in cardiac electrical activity showed that in human ventricular compartment, IRX5 expression strongly correlated to the expression of major actors of cardiac conduction, including the sodium channel, Nav1.5, and Connexin 40 (Cx40). We then generated human-induced pluripotent stem cells (hiPSCs) derived from two Hamamy syndrome-affected patients carrying distinct homozygous loss-of-function mutations in IRX5 gene. Cardiomyocytes derived from these hiPSCs showed impaired cardiac gene expression programme, including misregulation in the control of Nav1.5 and Cx40 expression. In accordance with the prolonged QRS interval observed in Hamamy syndrome patients, a slower ventricular action potential depolarization due to sodium current reduction was observed on electrophysiological analyses performed on patient-derived cardiomyocytes, confirming the functional role of IRX5 in electrical conduction. Finally, a cardiac TF complex was newly identified, composed by IRX5 and GATA4, in which IRX5 potentiated GATA4-induction of SCN5A expression. Conclusion: altogether, this work unveils a key role for IRX5 in the regulation of human ventricular depolarization and cardiac electrical conduction, providing therefore new insights into our understanding of cardiac diseases., National Research Agency; European Union (EU); Horizon 2020; Marie Curie Actions International Incoming Fellowship FP7-PEOPLE-2012-IIF; La Fédération Française de Cardiologie; Fondation LefoulonDelalande; Eiffel Scholarship Programme of Excellence (Campus France), Doctoral School of Science and Technology-Lebanese University and The Fondation Genavie

Published
2020

2. A consistent arrhythmogenic trait in Brugada syndrome cellular phenotype

Author

Aude Derevier, Robin Canac, Isabelle Baró, Guillaume Lamirault, Vincent Probst, Jean-Jacques Schott, Anne Gaignerie, Aurore Girardeau, Richard Redon, Julien Barc, Flavien Charpentier, Bastien Cimarosti, Patricia Lemarchand, Nathalie Gaborit, Virginie Forest, Zeina R Al Sayed, Nadjet Belbachir, Mariam Jouni, Gildas Loussouarn, Kazem Zibara, Pierre Olchesqui, Eric Charpentier, Jean-Baptiste Gourraud, Caroline Chariau, unité de recherche de l'institut du thorax UMR1087 UMR6291 (ITX), Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Structure fédérative de recherche François Bonamy (SFR François Bonamy), Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche en Santé de l'Université de Nantes (IRS-UN), Lebanese University [Beirut] (LU), gaborit, nathalie, Unité de recherche de l'institut du thorax (ITX-lab), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), and Université de Nantes (UN)-Université de Nantes (UN)

Subjects
Medicine (General), Heart Ventricles, [SDV]Life Sciences [q-bio], Induced Pluripotent Stem Cells, Medicine (miscellaneous), 030204 cardiovascular system & hematology, Letter to Editor, NAV1.5 Voltage-Gated Sodium Channel, 03 medical and health sciences, R5-920, 0302 clinical medicine, Text mining, Humans, Medicine, Myocytes, Cardiac, ComputingMilieux_MISCELLANEOUS, Brugada Syndrome, 030304 developmental biology, Brugada syndrome, Genetics, 0303 health sciences, business.industry, Gene Expression Profiling, Sodium, Electric Conductivity, Arrhythmias, Cardiac, medicine.disease, Cellular phenotype, [SDV] Life Sciences [q-bio], Phenotype, Gene Expression Regulation, Case-Control Studies, Mutation, Trait, Molecular Medicine, business, Biomarkers
Abstract

International audience

Published
2021

3. RRAD mutation causes electrical and cytoskeletal defects in cardiomyocytes derived from a familial case of Brugada syndrome

Author

Zeina R Al Sayed, Sabine Pattier, Hongchao Guo, Floriane Simonet, Solena Le Scouarnec, Emmanuelle Génin, Laurent David, Flavien Charpentier, Jean-Baptiste Gourraud, Caroline Chariau, Anne Gaignerie, Haodi Wu, Vincent Probst, Jean-François Deleuze, Stéphanie Bonnaud, Carol Scott, Florian Dilasser, Jean-Jacques Schott, Gervaise Loirand, Joseph C. Wu, Christian Dina, Isabelle Baró, Aurore Girardeau, Christophe Guilluy, Richard Redon, Vincent Sauzeau, Nathalie Gaborit, Sophie Burel, Matilde Karakachoff, Nadjet Belbachir, Laurence Jesel, Céline Marionneau, Vincent Portero, unité de recherche de l'institut du thorax UMR1087 UMR6291 (ITX), Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Genetic and Cellular Engineering in Immunology and Regenerative Medicine (Team 2 - U1064 Inserm - CRTI), Centre de Recherche en Transplantation et Immunologie (U1064 Inserm - CRTI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), Unité de recherche de l'institut du thorax (ITX-lab), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), and Le Bihan, Sylvie

Subjects
RAD GTPase, 030204 cardiovascular system & hematology, medicine.disease_cause, Afterdepolarization, 03 medical and health sciences, 0302 clinical medicine, Basic Science, Medicine, Missense mutation, Brugada syndrome, Induced pluripotent stem cell, Endocardium, 030304 developmental biology, 0303 health sciences, Mutation, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, business.industry, L-type calcium current, Actin cytoskeleton, medicine.disease, Cell biology, Electrophysiology, Induced pluripotent stem cells, Sodium current, Cardiology and Cardiovascular Medicine, business, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract

Aims The Brugada syndrome (BrS) is an inherited cardiac disorder predisposing to ventricular arrhythmias. Despite considerable efforts, its genetic basis and cellular mechanisms remain largely unknown. The objective of this study was to identify a new susceptibility gene for BrS through familial investigation. Methods and results Whole-exome sequencing performed in a three-generation pedigree with five affected members allowed the identification of one rare non-synonymous substitution (p.R211H) in RRAD, the gene encoding the RAD GTPase, carried by all affected members of the family. Three additional rare missense variants were found in 3/186 unrelated index cases. We detected higher levels of RRAD transcripts in subepicardium than in subendocardium in human heart, and in the right ventricle outflow tract compared to the other cardiac compartments in mice. The p.R211H variant was then subjected to electrophysiological and structural investigations in human cardiomyocytes derived from induced pluripotent stem cells (iPSC-CMs). Cardiomyocytes derived from induced pluripotent stem cells from two affected family members exhibited reduced action potential upstroke velocity, prolonged action potentials and increased incidence of early afterdepolarizations, with decreased Na+ peak current amplitude and increased Na+ persistent current amplitude, as well as abnormal distribution of actin and less focal adhesions, compared with intra-familial control iPSC-CMs Insertion of p.R211H-RRAD variant in control iPSCs by genome editing confirmed these results. In addition, iPSC-CMs from affected patients exhibited a decreased L-type Ca2+ current amplitude. Conclusion This study identified a potential new BrS-susceptibility gene, RRAD. Cardiomyocytes derived from induced pluripotent stem cells expressing RRAD variant recapitulated single-cell electrophysiological features of BrS, including altered Na+ current, as well as cytoskeleton disturbances.

Published
2019

4. HIV-Tat induces a decrease in I Kr and I Ks via reduction in phosphatidylinositol-(4,5)-bisphosphate availability

Author

Flavien Charpentier, Olfat A. Malak, Nadjet Belbachir, Mariam Jouni, C. Gauthier, Isabelle Baró, Kazem Zibara, Guillaume Lamirault, Zeina R Al Sayed, Bruno Beaumelle, Nathalie Gaborit, Zeineb Es-Salah-Lamoureux, Marine Gandon-Renard, Patricia Lemarchand, Gildas Loussouarn, unité de recherche de l'institut du thorax UMR1087 UMR6291 (ITX), Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre d’Investigation Clinique de Nantes (CIC Nantes), Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre hospitalier universitaire de Nantes (CHU Nantes), Laboratory of Stem Cells [Lebanese, Beirut] (ER045-PRASE), Lebanese University [Beirut] (LU), Institut de Recherche en Infectiologie de Montpellier (IRIM), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), This work was funded by grants from the Fédération Française de Cardiologie, the Fondation Genavie, the Marie Curie European Actions (PIIF-GA-2012-331436 and PIOF-GA-2011-298280), the French Regional Council of Pays-de-la-Loire (Regional grant VACARME -www.vacarme-project.org) and the Agence Nationale de Recherche (ANR-15-CE14-0019-01). Dr Z. Es-Salah-Lamoureux was supported by grants from the Lefoulon Delalande Foundation, the Fondation pour la Recherche Médicale (SPF20111223614, FRM) and the Fondation Genavie. M. Jouni was awarded a scholarship from the Association of Scientific Orientation and Specialization (ASOS). Olfat Malak was laureate of the Line Pomaret-Delalande prize of the Fondation pour la Recherche Médicale (PLP20141031304, FRM). Zeina Reda Al Sayed was awarded by a Eiffel program from Campus France., Centre d’études d’Agents Pathogènes et Biotechologies pour la Santé (CPBS), Unité de recherche de l'institut du thorax (ITX-lab), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), and Lemarchand, Patricia

Subjects
0301 basic medicine, Long QT syndrome, Mutant, hERG, Biophysics, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, 010402 general chemistry, 01 natural sciences, 03 medical and health sciences, Transactivation, chemistry.chemical_compound, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, medicine, Induced pluripotent stem cell, [SDV.BC] Life Sciences [q-bio]/Cellular Biology, Molecular Biology, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, 0303 health sciences, biology, Transfection, medicine.disease, Virology, 0104 chemical sciences, 3. Good health, Cell biology, 030104 developmental biology, Phosphatidylinositol 4,5-bisphosphate, chemistry, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, biology.protein, Heterologous expression, Cardiology and Cardiovascular Medicine
Abstract

International audience; Patients with HIV present with a higher prevalence of QT prolongation, of which molecularbases are still not clear. Among HIV proteins, Tat serves as a transactivator that stimulatesviral genes expression and is required for efficient HIV replication. Tat is actively secretedinto the blood by infected T-cells and affects organs such as the heart. Tat has been shown toalter cardiac repolarization in animal models but how this is mediated and whether this is alsothe case in human cells is unknown. In the present study, we show that Tat transfection inheterologous expression systems led to a decrease in hERG (underlying cardiac IKr) andhuman KCNE1-KCNQ1 (underlying cardiac IKs) currents and to an acceleration of theirdeactivation. This is consistent with a decrease in available phosphatidylinositol-(4,5)-bisphosphate (PIP2). A mutant Tat, unable to bind PIP2, did not reproduce the observedeffects. In addition, WT-Tat had no effect on a mutant KCNQ1 which is PIP2-insensitive,further confirming the hypothesis. Twenty four-hour incubation of human induced pluripotentstem cells-derived cardiomyocytes with Wild-type Tat reduced IKr and accelerated itsdeactivation. Concordantly, this Tat incubation led to a prolongation of the action potential(AP) duration. Events of AP alternans were also recorded in the presence of Tat, and wereexacerbated at a low pacing cycle length. Altogether, these data obtained on human K+channels both in heterologous expression systems and in human cardiomyocytes stronglysuggest that Tat sequesters PIP2, leading to a reduction of IKr and IKs, and provide a molecularmechanism for QT prolongation in HIV-infected patients.Key

Published
2016

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