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1. Variants in the GPR146 Gene Are Associated With a Favorable Cardiometabolic Risk Profile

Author

Rimbert, Antoine, Yeung, Ming W., Dalila, Nawar, Thio, Chris H.L., Yu, Haojie, Loaiza, Natalia, Oldoni, Federico, van der Graaf, Adriaan, Wang, Siqi, Said, M. Abdullah, Blauw, Lisanne L., Girardeau, Aurore, Bray, Lise, Caillaud, Amandine, Bloks, Vincent W., Marrec, Marie, Mouli, Philippe, Rensen, Patrick C.N., van de Sluis, Bart, Snieder, Harold, Di Filippo, Mathilde, van der Harst, Pim, Tybjaerg-Hansen, Anne, Zimmerman, Philippe, Cariou, Bertrand, and Kuivenhoven, Jan

Published
2022
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2. Human induced pluripotent stem cells‐derived liver organoids grown on a Biomimesys® hyaluronic acid‐based hydroscaffold as a new model for studying human lipoprotein metabolism

Author

Roudaut, Meryl, primary, Caillaud, Amandine, additional, Souguir, Zied, additional, Bray, Lise, additional, Girardeau, Aurore, additional, Rimbert, Antoine, additional, Croyal, Mikaël, additional, Lambert, Gilles, additional, Patitucci, Murielle, additional, Delpouve, Gaspard, additional, Vandenhaute, Élodie, additional, Le May, Cédric, additional, Maubon, Nathalie, additional, Cariou, Bertrand, additional, and Si‐Tayeb, Karim, additional

Published
2024
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4. Benefice of the stimulation of O-GlcNAcylation on sodium potassium pump during hemorrhagic shock

Author

Vergnaud, Amandine, primary, Dupas, Thomas, additional, Aillerie, Virginie, additional, Persello, Antoine, additional, Pele, Thomas, additional, Blangy-Letheule, Angélique, additional, Erraud, Angelique, additional, Girardeau, Aurore, additional, Ribeiro, Barbara, additional, Montnach, Jérôme, additional, De Waard, Michel, additional, Rozec, Bertrand, additional, and Lauzier, Benjamin, additional

Published
2023
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5. Deciphering Transcriptional Networks during Human Cardiac Development

Author

Canac, Robin, primary, Cimarosti, Bastien, additional, Girardeau, Aurore, additional, Forest, Virginie, additional, Olchesqui, Pierre, additional, Poschmann, Jeremie, additional, Redon, Richard, additional, Lemarchand, Patricia, additional, Gaborit, Nathalie, additional, and Lamirault, Guillaume, additional

Published
2022
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6. FACS-assisted CRISPR-Cas9 genome editing of human induced pluripotent stem cells

Author

Caillaud, Amandine, primary, Lévêque, Antoine, additional, Thédrez, Aurélie, additional, Girardeau, Aurore, additional, Canac, Robin, additional, Bray, Lise, additional, Baudic, Manon, additional, Barc, Julien, additional, Gaborit, Nathalie, additional, Lamirault, Guillaume, additional, Gardie, Betty, additional, Idriss, Salam, additional, Rimbert, Antoine, additional, Le May, Cédric, additional, Cariou, Bertrand, additional, and Si-Tayeb, Karim, additional

Published
2022
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7. Variants in theGPR146Gene Are Associated With a Favorable Cardiometabolic Risk Profile

Author

Rimbert, Antoine, primary, Yeung, Ming W., additional, Dalila, Nawar, additional, Thio, Chris H.L., additional, Yu, Haojie, additional, Loaiza, Natalia, additional, Oldoni, Federico, additional, van der Graaf, Adriaan, additional, Wang, Siqi, additional, Said, M. Abdullah, additional, Blauw, Lisanne L., additional, Girardeau, Aurore, additional, Bray, Lise, additional, Caillaud, Amandine, additional, Bloks, Vincent W., additional, Marrec, Marie, additional, Moulin, Philippe, additional, Rensen, Patrick C.N., additional, van de Sluis, Bart, additional, Snieder, Harold, additional, Di Filippo, Mathilde, additional, van der Harst, Pim, additional, Tybjaerg-Hansen, Anne, additional, Zimmerman, Philip, additional, Cariou, Bertrand, additional, and Kuivenhoven, Jan Albert, additional

Published
2022
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9. Generation of three human induced pluripotent stem cell lines with IRX5 knockout and knockin genetic editions using CRISPR-Cas9 system

Author

Reversade, Bruno, Canac, Robin; Caillaud, Amandine; Cimarosti, Bastien; Girardeau, Aurore; Hamamy, Hanan; Bonnard, Carine; Al Sayed, Zeina R.; David, Laurent; Poschmann, Jeremie; Lemarchand, Patricia; Lamirault, Guillaume; Gaborit, Nathalie, School of Medicine, Reversade, Bruno, Canac, Robin; Caillaud, Amandine; Cimarosti, Bastien; Girardeau, Aurore; Hamamy, Hanan; Bonnard, Carine; Al Sayed, Zeina R.; David, Laurent; Poschmann, Jeremie; Lemarchand, Patricia; Lamirault, Guillaume; Gaborit, Nathalie, and School of Medicine

Abstract

Studies on animal models have shown that Irx5 is an important regulator of cardiac development and that it regulates ventricular electrical repolarization gradient in the adult heart. Mutations in IRX5 have also been linked in humans to cardiac conduction defects. In order to fully characterize the role of IRX5 during cardiac development and in cardiomyocyte function, we generated three genetically-modified human induced pluripotent stem cell lines: two knockout lines (heterozygous and homozygous) and a knockin HA-tagged line (homozygous)., French National Research Agency; La Fédération Française de Cardiologie; Fondation Lefoulon-Delalande; Marie Curie Inter-national Incoming Fellowship FP7-PEOPLE-2012-IIF; Marion Elizabeth Brancher (MEB)

Published
2022

10. Variants in the GPR146 Gene Are Associated With a Favorable Cardiometabolic Risk Profile.

Author

Team Onderzoek, Gezonde Vaten, Circulatory Health, Team Medisch, Rimbert, Antoine, Yeung, Ming W, Dalila, Nawar, Thio, Chris H L, Yu, Haojie, Loaiza, Natalia, Oldoni, Federico, van der Graaf, Adriaan, Wang, Siqi, Said, M Abdullah, Blauw, Lisanne L, Girardeau, Aurore, Bray, Lise, Caillaud, Amandine, Bloks, Vincent W, Marrec, Marie, Moulin, Philippe, Rensen, Patrick C N, van de Sluis, Bart, Snieder, Harold, Di Filippo, Mathilde, van der Harst, Pim, Tybjaerg-Hansen, Anne, Zimmerman, Philip, Cariou, Bertrand, Kuivenhoven, Jan Albert, Team Onderzoek, Gezonde Vaten, Circulatory Health, Team Medisch, Rimbert, Antoine, Yeung, Ming W, Dalila, Nawar, Thio, Chris H L, Yu, Haojie, Loaiza, Natalia, Oldoni, Federico, van der Graaf, Adriaan, Wang, Siqi, Said, M Abdullah, Blauw, Lisanne L, Girardeau, Aurore, Bray, Lise, Caillaud, Amandine, Bloks, Vincent W, Marrec, Marie, Moulin, Philippe, Rensen, Patrick C N, van de Sluis, Bart, Snieder, Harold, Di Filippo, Mathilde, van der Harst, Pim, Tybjaerg-Hansen, Anne, Zimmerman, Philip, Cariou, Bertrand, and Kuivenhoven, Jan Albert

Published
2022

12. Generation of human induced pluripotent stem cell lines from three patients affected by Catecholaminergic Polymorphic ventricular tachycardia (CPVT) carrying heterozygous mutations in RYR2 gene

Author

Cimarosti, Bastien, primary, Canac, Robin, additional, De Waard, Stephan, additional, Girardeau, Aurore, additional, Gaignerie, Anne, additional, Derevier, Aude, additional, Forest, Virginie, additional, Ronjat, Michel, additional, Le Marec, Hervé, additional, Gourraud, Jean-Baptiste, additional, Lemarchand, Patricia, additional, De Waard, Michel, additional, Lamirault, Guillaume, additional, and Gaborit, Nathalie, additional

Published
2022
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14. Generation of human induced pluripotent stem cell lines from two patients affected by catecholamine-induced QT prolongation (CIQTP)

Author

Cimarosti, Bastien, primary, Canac, Robin, additional, Girardeau, Aurore, additional, Arnaud, Marine, additional, Francheteau, Quentin, additional, Probst, Vincent, additional, Lemarchand, Patricia, additional, Redon, Richard, additional, Gourraud, Jean-Baptiste, additional, Gaborit, Nathalie, additional, and Lamirault, Guillaume, additional

Published
2022
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15. Generation of human induced pluripotent stem cell lines from four unrelated healthy control donors carrying European genetic background

Author

Girardeau, Aurore, primary, Atticus, Diane, additional, Canac, Robin, additional, Cimarosti, Bastien, additional, Caillaud, Amandine, additional, Chariau, Caroline, additional, Simonet, Floriane, additional, Cariou, Bertrand, additional, Charpentier, Flavien, additional, Gourraud, Jean-Baptiste, additional, Probst, Vincent, additional, Belbachir, Nadjet, additional, Jesel, Laurence, additional, Lemarchand, Patricia, additional, Barc, Julien, additional, Redon, Richard, additional, Gaborit, Nathalie, additional, and Lamirault, Guillaume, additional

Published
2022
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16. Generation of three human induced pluripotent stem cell lines with IRX5 knockout and knockin genetic editions using CRISPR-Cas9 system

Author

Canac, Robin, primary, Caillaud, Amandine, additional, Cimarosti, Bastien, additional, Girardeau, Aurore, additional, Hamamy, Hanan, additional, Reversade, Bruno, additional, Bonnard, Carine, additional, Al Sayed, Zeina R., additional, David, Laurent, additional, Poschmann, Jeremie, additional, Lemarchand, Patricia, additional, Lamirault, Guillaume, additional, and Gaborit, Nathalie, additional

Published
2022
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17. PCSK9 regulates the NODAL signaling pathway and cellular proliferation in hiPSCs

Author

Roudaut, Meryl, primary, Idriss, Salam, additional, Caillaud, Amandine, additional, Girardeau, Aurore, additional, Rimbert, Antoine, additional, Champon, Benoite, additional, David, Amandine, additional, Lévêque, Antoine, additional, Arnaud, Lucie, additional, Pichelin, Matthieu, additional, Prieur, Xavier, additional, Prat, Annik, additional, Seidah, Nabil G., additional, Zibara, Kazem, additional, Le May, Cedric, additional, Cariou, Bertrand, additional, and Si-Tayeb, Karim, additional

Published
2021
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20. A consistent arrhythmogenic trait in Brugada syndrome cellular phenotype

Author

Al Sayed, Zeina R., primary, Jouni, Mariam, additional, Gourraud, Jean‐Baptiste, additional, Belbachir, Nadjet, additional, Barc, Julien, additional, Girardeau, Aurore, additional, Forest, Virginie, additional, Derevier, Aude, additional, Gaignerie, Anne, additional, Chariau, Caroline, additional, Cimarosti, Bastien, additional, Canac, Robin, additional, Olchesqui, Pierre, additional, Charpentier, Eric, additional, Schott, Jean‐Jacques, additional, Redon, Richard, additional, Baró, Isabelle, additional, Probst, Vincent, additional, Charpentier, Flavien, additional, Loussouarn, Gildas, additional, Zibara, Kazem, additional, Lamirault, Guillaume, additional, Lemarchand, Patricia, additional, and Gaborit, Nathalie, additional

Published
2021
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21. Human model of IRX5 mutations reveals key role for this transcription factor in ventricular conduction

Author

School of Medicine, 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, Karabey, Hülya Kayserili (ORCID 0000-0003-0376-499X & YÖK ID 7945); Reversade, Bruno, and 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

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.

Published
2020

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

Author

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, 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, and School of Medicine

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

23. Variants in the GPR146Gene Are Associated With a Favorable Cardiometabolic Risk Profile

Author

Rimbert, Antoine, Yeung, Ming W., Dalila, Nawar, Thio, Chris H.L., Yu, Haojie, Loaiza, Natalia, Oldoni, Federico, van der Graaf, Adriaan, Wang, Siqi, Said, M. Abdullah, Blauw, Lisanne L., Girardeau, Aurore, Bray, Lise, Caillaud, Amandine, Bloks, Vincent W., Marrec, Marie, Moulin, Philippe, Rensen, Patrick C.N., van de Sluis, Bart, Snieder, Harold, Di Filippo, Mathilde, van der Harst, Pim, Tybjaerg-Hansen, Anne, Zimmerman, Philip, Cariou, Bertrand, and Kuivenhoven, Jan Albert

Published
2022
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24. Human model of IRX5 mutations reveals key role for this transcription factor in ventricular conduction

Author

Al Sayed, Zeina R, primary, Canac, Robin, additional, Cimarosti, Bastien, additional, Bonnard, Carine, additional, Gourraud, Jean-Baptiste, additional, Hamamy, Hanan, additional, Kayserili, Hulya, additional, Girardeau, Aurore, additional, Jouni, Mariam, additional, Jacob, Nicolas, additional, Gaignerie, Anne, additional, Chariau, Caroline, additional, David, Laurent, additional, Forest, Virginie, additional, Marionneau, Céline, additional, Charpentier, Flavien, additional, Loussouarn, Gildas, additional, Lamirault, Guillaume, additional, Reversade, Bruno, additional, Zibara, Kazem, additional, Lemarchand, Patricia, additional, and Gaborit, Nathalie, additional

Published
2020
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25. Human model of IRX5 mutations reveals key role for this transcription factor in ventricular conduction.

Author

Sayed, Zeina R Al, Canac, Robin, Cimarosti, Bastien, Bonnard, Carine, Gourraud, Jean-Baptiste, Hamamy, Hanan, Kayserili, Hulya, Girardeau, Aurore, Jouni, Mariam, Jacob, Nicolas, Gaignerie, Anne, Chariau, Caroline, David, Laurent, Forest, Virginie, Marionneau, Céline, Charpentier, Flavien, Loussouarn, Gildas, Lamirault, Guillaume, Reversade, Bruno, and Zibara, Kazem

Subjects
BRUGADA syndrome, TRANSCRIPTION factors, PLURIPOTENT stem cells, SODIUM channels, ION channels, GENETIC mutation
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. [ABSTRACT FROM AUTHOR]

Published
2021
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26. RRAD mutation causes electrical and cytoskeletal defects in cardiomyocytes derived from a familial case of Brugada syndrome

Author

Belbachir, Nadjet, primary, Portero, Vincent, additional, Al Sayed, Zeina R, additional, Gourraud, Jean-Baptiste, additional, Dilasser, Florian, additional, Jesel, Laurence, additional, Guo, Hongchao, additional, Wu, Haodi, additional, Gaborit, Nathalie, additional, Guilluy, Christophe, additional, Girardeau, Aurore, additional, Bonnaud, Stephanie, additional, Simonet, Floriane, additional, Karakachoff, Matilde, additional, Pattier, Sabine, additional, Scott, Carol, additional, Burel, Sophie, additional, Marionneau, Céline, additional, Chariau, Caroline, additional, Gaignerie, Anne, additional, David, Laurent, additional, Genin, Emmanuelle, additional, Deleuze, Jean-François, additional, Dina, Christian, additional, Sauzeau, Vincent, additional, Loirand, Gervaise, additional, Baró, Isabelle, additional, Schott, Jean-Jacques, additional, Probst, Vincent, additional, Wu, Joseph C, additional, Redon, Richard, additional, Charpentier, Flavien, additional, and Le Scouarnec, Solena, additional

Published
2019
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28. T Cells Promote Bronchial Epithelial Cell Secretion of Matrix Metalloproteinase-9 via a C-C Chemokine Receptor Type 2 Pathway: Implications for Chronic Lung Allograft Dysfunction

Author

Pain, Mallory, Royer, Pierre-Joseph, Loy, Jennifer, Girardeau, Aurore, Tissot, A., Lacoste, P., Roux, A., Reynaud-Gaubert, M., Kessler, R., Mussot, S., Dromer, C., Brugiere, O., Mornex, J. -F., Guillemain, R., Dahan, M., Knoop, C., Botturi, Karine, Pison, C., Danger, R., Brouard, S., Magnan, Antoine, Consortium, COLT, 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), CTG - Italcementi Group, Ciments CALCIA-Italcementi Group, Unité de Recherche sur les Maladies Infectieuses et Tropicales Emergentes (URMITE), Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR48, INSB-INSB-Centre National de la Recherche Scientifique (CNRS), Service de Pneumologie, Nouvel Hôpital Civil Strasbourg, Laboratory of Fundamental and Applied Bioenergetics = Laboratoire de bioénergétique fondamentale et appliquée (LBFA), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Centre Hospitalier Universitaire [Grenoble] (CHU), 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), Association Vaincre la Mucoviscidose, Agence de la Biomédecine, Fonds de Recherche en Santé Respiratoire, Fondation du Souffle, French government, Nantes Métropole and Région Pays de la Loire, Institut National de la Santé et de la Recherche Médicale, Fondation pour la Recherche Médicale, ANR-10-IBHU-005, Agence Nationale de la Recherche, Association Gregory Lemarchal, Région Pays de La Loire, Institut de Recherche en Santé Respiratoire des Pays de la Loire, 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 Institut des sciences biologiques (INSB-CNRS)-Institut des sciences biologiques (INSB-CNRS)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Graft Rejection, Lung Diseases, Male, 0301 basic medicine, Chemokine, translational research/science, T-Lymphocytes, 030230 surgery, Matrix metalloproteinase, Chemokine receptor, Postoperative Complications, 0302 clinical medicine, lung transplantation/pulmonology, Risk Factors, Transforming Growth Factor beta, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Immunology and Allergy, Medicine, Pharmacology (medical), Longitudinal Studies, Epithelial cell differentiation, biology, Graft Survival, Middle Aged, Allografts, Prognosis, Matrix Metalloproteinase 9, Cytokines, Female, Lung Transplantation, Adult, Receptors, CCR2, Bronchi, Proinflammatory cytokine, 03 medical and health sciences, Immune system, Humans, Secretion, Transplantation, business.industry, rejection: chronic, Epithelial Cells, Transforming growth factor beta, 030104 developmental biology, lung (allograft) function/dysfunction, Chronic Disease, Immunology, biology.protein, business, bronchiolitis obliterans (BOS), Biomarkers, Follow-Up Studies
Abstract

International audience; Chronic lung allograft dysfunction (CLAD) is the major limitation of long-term survival after lung transplantation. CLAD manifests as bronchiolitis obliterans syndrome (BOS) or restrictive allograft syndrome (RAS). Alloimmune reactions and epithelial-to-mesenchymal transition have been suggested in BOS. However, little is known regarding the role of allogenicity in epithelial cell differentiation. Primary human bronchial epithelial cells (BECs) were treated with activated T cells in the presence or absence of transforming growth factor (TGF)-beta. The expression of epithelial and mesenchymal markers was investigated. The secretion of inflammatory cytokines and matrix metalloproteinase (MMP)-9 was measured in culture supernatants and in plasma from lung transplant recipients (LTRs): 49 stable, 29 with BOS, and 16 with RAS. We demonstrated that C-C motif chemokine 2 secreted by T cells supports TGF-beta-induced MMP-9 production by BECs after binding to C-C chemokine receptor type 2. Longitudinal investigation in LTRs revealed a rise in plasma MMP-9 before CLAD onset. Multivariate analysis showed that plasma MMP-9 was independently associated with BOS (odds ratio [OR] = 6.19, p = 0.002) or RAS (OR = 3.9, p = 0.024) and predicted the occurrence of CLAD 12 months before the functional diagnosis. Thus, immune cells support airway remodeling through the production of MMP-9. Plasma MMP-9 is a potential predictive biomarker of CLAD.

Published
2017

30. Mutant voltage-gated Na+ channels can exert a dominant negative effect through coupled gating.

Author

Clatot, Jérôme, Yang Zheng, Girardeau, Aurore, Haiyan Liu, Laurita, Kenneth R., Marionneau, Céline, and Deschênes, Isabelle

Abstract

Mutations in voltagegated Naα channels have been linked to several channelopathies leading to a wide variety of diseases including cardiac arrhythmias, epilepsy, and myotonia. We have previously demonstrated that voltage- gated Na± channel (Nav)1.5 trafficking-deficient mutant channels could lead to a dominant negative effect by impairing trafficking of the wild-type (WT) channel. We also reported that voltage-gated Na± channels associate as dimers with coupled gating properties. Here, we hypothesized that the dominant negative effect of mutant Na± channels could also occur through coupled gating. This was tested using cell surface biotinylation and single channel recordings to measure the gating probability and coupled gating of the dimers. As previously reported, coexpression of Nav1.5-L325R with WT channels led to a dominant negative effect, as reflected by a 75% reduction in current density. Surprisingly, cell surface biotinylation showed that Nav1.5- L325R mutant is capable of trafficking, with 40% of Nav1.5-L325R reaching the cell surface when expressed alone. Importantly, even though a dominant negative effect on the Na± current is observed when WT and Nav1.5-L325R are expressed together, the total Nav channel cell surface expression was not significantly altered compared with WT channels alone. Thus, the trafficking deficiency could not explain the 75% decrease in inward Na± current. Interestingly, single channel recordings showed that Nav1.5-L325R exerted a dominant negative effect on the WT channel at the gating level. Both coupled gating and gating probability of WT:L325R dimers were drastically impaired. We conclude that dominant negative suppression exerted by Nav1.5 mutants can also be caused by impairing the WT gating probability, a mechanism resulting from the dimerization and coupled gating of voltage-gated Na± channel α-subunits. [ABSTRACT FROM AUTHOR]

Published
2018
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31. Transforming growth factor @#946; receptor inhibition prevents ventricular fibrosis in a mouse model of progressive cardiac conduction disease.

Author

Derangeon, Mickael, Montnach, Jérôme, Cerpa, Cynthia Ore, Jagu, Benoit, Patin, Justine, Toumaniantz, Gilles, Girardeau, Aurore, Huang, Christopher L. H., Colledge, William H., Grace, Andrew A., Barö, Isabelle, and Charpentier, Flavien

Subjects
TRANSFORMING growth factor receptors, FIBROSIS, HEART conduction system, GENETIC mutation, SMAD proteins, DISEASES, PREVENTION
Abstract

Aims: Loss-of-function mutations in SCN5A, the gene encoding Nav1.5 channel, have been associated with inherited progressive cardiac conduction disease (PCCD). We have proposed that Scri5o heterozygous l+/-) mice, which are characterized by ventricular fibrotic remodelling with ageing, represent a model for PCCD. Our objectives were to identify the molecular pathway involved in fibrosis development and prevent its activation. Conclusion: Methods and results: Our study shows that myocardial interstitial fibrosis occurred in Scn.5ö+/- mice only after 45 weeks of age. Fibrosis was triggered by transforming growth factor β (TGF-β) pathway activation. Younger Scn5o+/- mice were characterized by a higher connexin 43 expression than wild-type (WT) mice. After the age of 45 weeks, connexin 43 expression decreased in both W T and Scn5a+/- mice, although the decrease was larger in Scn5o+/- mice. Chronic inhibition of cardiac sodium current with flecainide (50mg/l+/- mice from the age of 45 weel+/- mouse. [ABSTRACT FROM AUTHOR]

Published
2017
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32. Abstract 13258: Transcriptomic Remodeling of Brugada Syndrome Arises During in vitroCardiac Development

Author

Cimarosti, Bastien, Canac, Robin, Forest, Virginie, Girardeau, Aurore, Gaborit, Nathalie, Lemarchand, Patricia, Redon, Richard, and Lamirault, Guillaume

Abstract

Introduction:Recent genetic data suggest that abnormal cardiac development participate to the pathogenesis of Brugada Syndrome (BrS), a rare inherited arrhythmia responsible for sudden cardiac death in young adults. In vitrocardiac differentiation of human induced pluripotent stem cells (hiPSCs) mimics cardiac development at the cellular level up to a prenatal stage.Objective:This study aims at defining whether BrS impairs cardiac differentiation of hiPSCs.Methods & Results:Transcriptomic kinetics (daily bulk 3’RNA-seq from day 0 to day 30 of in vitro cardiac differentiation) were generated in triplicate for 2 control hiPSC lines and 2 BrS-patient hiPSC lines. First, global analysis unveiled that BrS and control kinetics start to diverge as early as day 8, coinciding with the emergence of beating cells. The 500 most differentially expressed genes between BrS and control kinetics revealed 7 main distinct expression profiles. Interestingly, in one of the clusters (Cluster 2), enriched in genes involved in ventricular development (e.g. IRX4, NKX2-5), the expression levels were higher in BrS as compared to control, starting at day 8. Inversely, another cluster (Cluster 4), enriched in genes involved in atrial development (e.g. TBX18, PITX2), displayed an opposite expression profile. Cell-type annotation of single-cell RNA-seq data obtained at day 30 of cardiac differentiation for 1 control (n=2; 11,499 cells) and 1 BrS hiPSCs line (n=2; 12,142 cells) confirmed this ventricular-to-atrial imbalance with an average ventricular-to-atrial cell number ratio of 0.97 and 8.27 for control and BrS lines, respectively.Conclusion:This first transcriptomic kinetic study supports the hypothesis of an early developmental defect in BrS. Altogether, our data show that BrS hiPSCs are more prone to ventricular specification as compared to control cells. This suggests that an abnormal cell fate during cardiac differentiation may participate to BrS pathogeny.

Published
2021
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33. 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

34. Generation of three human induced pluripotent stem cell lines with IRX5 knockout and knockin genetic editions using CRISPR-Cas9 system

Author

Robin Canac, Amandine Caillaud, Bastien Cimarosti, Aurore Girardeau, Hanan Hamamy, Bruno Reversade, Carine Bonnard, Zeina R. Al Sayed, Laurent David, Jeremie Poschmann, Patricia Lemarchand, Guillaume Lamirault, Nathalie Gaborit, Center for Reproductive Medicine, Reversade, Bruno, Canac, Robin, Caillaud, Amandine, Cimarosti, Bastien, Girardeau, Aurore, Hamamy, Hanan, Bonnard, Carine, Al Sayed, Zeina R., David, Laurent, Poschmann, Jeremie, Lemarchand, Patricia, Lamirault, Guillaume, 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)-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), Centre hospitalier universitaire de Nantes (CHU Nantes), Université de Genève = University of Geneva (UNIGE), Genome Institute of Singapore (GIS), Amsterdam UMC - Amsterdam University Medical Center, Agency for science, technology and research [Singapore] (A*STAR), 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 (Nantes Univ), 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), and gaborit, nathalie

Subjects
Homeodomain Proteins, Heterozygote, [SDV.BIO]Life Sciences [q-bio]/Biotechnology, QH301-705.5, Homozygote, Induced Pluripotent Stem Cells, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Cell Biology, General Medicine, Homeobox genes, Transcription Factor, Liver cell carcinoma, [SDV.BIO] Life Sciences [q-bio]/Biotechnology, Genetics, cardiovascular system, Animals, Humans, Myocytes, Cardiac, Biology (General), CRISPR-Cas Systems, [SDV.BC] Life Sciences [q-bio]/Cellular Biology, Transcription Factors, Developmental Biology
Abstract

Studies on animal models have shown that Irx5 is an important regulator of cardiac development and that it regulates ventricular electrical repolarization gradient in the adult heart. Mutations in IRX5 have also been linked in humans to cardiac conduction defects. In order to fully characterize the role of IRX5 during cardiac development and in cardiomyocyte function, we generated three genetically-modified human induced pluripotent stem cell lines: two knockout lines (heterozygous and homozygous) and a knockin HA-tagged line (homozygous)., French National Research Agency; La Fédération Française de Cardiologie; Fondation Lefoulon-Delalande; Marie Curie Inter-national Incoming Fellowship FP7-PEOPLE-2012-IIF; Marion Elizabeth Brancher (MEB)

Published
2022

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

Author

Al Sayed ZR, Canac R, Cimarosti B, Bonnard C, Gourraud JB, Hamamy H, Kayserili H, Girardeau A, Jouni M, Jacob N, Gaignerie A, Chariau C, David L, Forest V, Marionneau C, Charpentier F, Loussouarn G, Lamirault G, Reversade B, Zibara K, Lemarchand P, and Gaborit N

Subjects
Animals, Arrhythmias, Cardiac metabolism, Arrhythmias, Cardiac physiopathology, Bone Diseases metabolism, Bone Diseases physiopathology, Cells, Cultured, Connexins genetics, Connexins metabolism, GATA4 Transcription Factor genetics, GATA4 Transcription Factor metabolism, Heart Rate, Homeodomain Proteins metabolism, Humans, Hypertelorism metabolism, Hypertelorism physiopathology, Intellectual Disability metabolism, Intellectual Disability physiopathology, Male, Mice, Inbred C57BL, Myopia metabolism, Myopia physiopathology, NAV1.5 Voltage-Gated Sodium Channel genetics, NAV1.5 Voltage-Gated Sodium Channel metabolism, Transcription Factors metabolism, Transcriptome, Gap Junction alpha-5 Protein, Mice, Action Potentials, Arrhythmias, Cardiac genetics, Bone Diseases genetics, Heart Ventricles metabolism, Homeodomain Proteins genetics, Hypertelorism genetics, Induced Pluripotent Stem Cells metabolism, Intellectual Disability genetics, Loss of Function Mutation, Myocytes, Cardiac metabolism, Myopia genetics, Transcription Factors genetics
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., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2020. For permissions, please email: journals.permissions@oup.com.)

Published
2021
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36. Mutant voltage-gated Na + channels can exert a dominant negative effect through coupled gating.

Author

Clatot J, Zheng Y, Girardeau A, Liu H, Laurita KR, Marionneau C, and Deschênes I

Subjects
Arrhythmias, Cardiac genetics, Arrhythmias, Cardiac metabolism, Arrhythmias, Cardiac physiopathology, HEK293 Cells, Heart Rate genetics, Humans, Markov Chains, Membrane Potentials, Models, Biological, Protein Multimerization, Protein Transport, Time Factors, Ion Channel Gating genetics, Mutation, NAV1.5 Voltage-Gated Sodium Channel genetics, NAV1.5 Voltage-Gated Sodium Channel metabolism, Sodium metabolism
Abstract

Mutations in voltage-gated Na + channels have been linked to several channelopathies leading to a wide variety of diseases including cardiac arrhythmias, epilepsy, and myotonia. We have previously demonstrated that voltage-gated Na + channel (Na v )1.5 trafficking-deficient mutant channels could lead to a dominant negative effect by impairing trafficking of the wild-type (WT) channel. We also reported that voltage-gated Na + channels associate as dimers with coupled gating properties. Here, we hypothesized that the dominant negative effect of mutant Na + channels could also occur through coupled gating. This was tested using cell surface biotinylation and single channel recordings to measure the gating probability and coupled gating of the dimers. As previously reported, coexpression of Na v 1.5-L325R with WT channels led to a dominant negative effect, as reflected by a 75% reduction in current density. Surprisingly, cell surface biotinylation showed that Na v 1.5-L325R mutant is capable of trafficking, with 40% of Na v 1.5-L325R reaching the cell surface when expressed alone. Importantly, even though a dominant negative effect on the Na + current is observed when WT and Na v 1.5-L325R are expressed together, the total Na v channel cell surface expression was not significantly altered compared with WT channels alone. Thus, the trafficking deficiency could not explain the 75% decrease in inward Na + current. Interestingly, single channel recordings showed that Na v 1.5-L325R exerted a dominant negative effect on the WT channel at the gating level. Both coupled gating and gating probability of WT:L325R dimers were drastically impaired. We conclude that dominant negative suppression exerted by Na v 1.5 mutants can also be caused by impairing the WT gating probability, a mechanism resulting from the dimerization and coupled gating of voltage-gated Na + channel α-subunits. NEW & NOTEWORTHY The presence of dominant negative mutations in the Na + channel gene leading to Brugada syndrome was supported by our recent findings that Na + channel α-subunits form dimers. Up until now, the dominant negative effect was thought to be caused by the interaction of the wild-type Na + channel with trafficking-deficient mutant channels. However, the present study demonstrates that coupled gating of voltage-gated Na + channels can also be responsible for the dominant negative effect leading to arrhythmias.

Published
2018
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