CAVIN1-Mediated hERG Dynamics: A Novel Mechanism Underlying the Interindividual Variability in Drug-Induced Long QT
| dc.rights.license | open | en_US |
| hal.structure.identifier | Paris-Centre de Recherche Cardiovasculaire [PARCC (UMR_S 970/ U970)] | |
| dc.contributor.author | AL SAYED, Zeina | |
| hal.structure.identifier | Paris-Centre de Recherche Cardiovasculaire [PARCC (UMR_S 970/ U970)] | |
| dc.contributor.author | PEREIRA, Céline | |
| hal.structure.identifier | Institut Jacques Monod [IJM (UMR_7592)] | |
| dc.contributor.author | LE BORGNE, Rémi | |
| hal.structure.identifier | Chimie biologique des membranes et ciblage thérapeutique [CBMCT - UMR 3666 / U1143] | |
| dc.contributor.author | VIARIS DE LESEGNO, Christine | |
| hal.structure.identifier | Paris-Centre de Recherche Cardiovasculaire [PARCC (UMR_S 970/ U970)] | |
| dc.contributor.author | JOUVE, Charlène | |
| hal.structure.identifier | Plate-forme de bioimagerie ultrastructurale - Ultrastructural BioImaging Core Facility | |
| dc.contributor.author | PÉNARD, Esthel | |
| hal.structure.identifier | Plate-forme de bioimagerie ultrastructurale - Ultrastructural BioImaging Core Facility | |
| dc.contributor.author | MALLET, Adeline | |
| hal.structure.identifier | Paris-Centre de Recherche Cardiovasculaire [PARCC (UMR_S 970/ U970)] | |
| dc.contributor.author | MASURKAR, Nihar | |
| hal.structure.identifier | Institut du Thorax [Nantes] | |
| dc.contributor.author | LOUSSOUARN, Gildas | |
| hal.structure.identifier | Institut Jacques Monod [IJM (UMR_7592)] | |
| dc.contributor.author | VERBAVATZ, Jean-Marc | |
| hal.structure.identifier | Chimie biologique des membranes et ciblage thérapeutique [CBMCT - UMR 3666 / U1143] | |
| dc.contributor.author | LAMAZE, Christophe | |
| hal.structure.identifier | Bordeaux population health [BPH] | |
| dc.contributor.author | TREGOUET, David-Alexandre | |
| hal.structure.identifier | Paris-Centre de Recherche Cardiovasculaire [PARCC (UMR_S 970/ U970)] | |
| hal.structure.identifier | CIC - HEGP [CIC 1418] | |
| dc.contributor.author | HULOT, Jean-Sébastien | |
| dc.date.accessioned | 2024-06-13T14:01:37Z | |
| dc.date.available | 2024-06-13T14:01:37Z | |
| dc.date.issued | 2024-04-29 | |
| dc.identifier.issn | 0009-7322 | en_US |
| dc.identifier.uri | https://oskar-bordeaux.fr/handle/20.500.12278/200466 | |
| dc.description.abstractEn | BACKGROUND: Drug-induced QT prolongation (diLQT) is a feared side effect that could expose susceptible individuals to fatal arrhythmias. The occurrence of diLQT is primarily attributed to unintended drug interactions with cardiac ion channels, notably the hERG (human ether-a-go-go-related gene) channels that generate the delayed-rectifier potassium current (I Kr ) and thereby regulate the late repolarization phase. There is an important interindividual susceptibility to develop diLQT, which is of unknown origin but can be reproduced in patient-specific induced pluripotent stem cell–derived cardiomyocytes (iPS-CMs). We aimed to investigate the dynamics of hERG channels in response to sotalol and to identify regulators of the susceptibility to developing diLQT. METHODS: We measured electrophysiological activity and cellular distribution of hERG channels after hERG blocker treatment in iPS-CMs derived from patients with highest sensitivity (HS) or lowest sensitivity (LS) to sotalol administration in vivo (ie, on the basis of the measure of the maximal change in QT interval 3 hours after administration). Specific small interfering RNAs and CAVIN1-T2A-GFP adenovirus were used to manipulate CAVIN1 expression. RESULTS: Whereas HS and LS iPS-CMs showed similar electrophysiological characteristics at baseline, the late repolarization phase was prolonged and I Kr significantly decreased after exposure of HS iPS-CMs to low sotalol concentrations. I Kr reduction was caused by a rapid translocation of hERG channel from the membrane to the cytoskeleton-associated fractions upon sotalol application. CAVIN1 , essential for caveolae biogenesis, was 2× more highly expressed in HS iPS-CMs, and its knockdown by small interfering RNA reduced their sensitivity to sotalol. CAVIN1 overexpression in LS iPS-CMs using adenovirus showed reciprocal effects. We found that treatment with sotalol promoted translocation of the hERG channel from the plasma membrane to the cytoskeleton fractions in a process dependent on CAVIN1 (caveolae associated protein 1) expression. CAVIN1 silencing reduced the number of caveolae at the membrane and abrogated the translocation of hERG channel in sotalol-treated HS iPS-CMs. CAVIN1 also controlled cardiomyocyte responses to other hERG blockers, such as E4031, vandetanib, and clarithromycin. CONCLUSIONS: Our study identifies unbridled turnover of the potassium channel hERG as a mechanism supporting the interindividual susceptibility underlying diLQT development and demonstrates how this phenomenon is finely tuned by CAVIN1. | |
| dc.description.sponsorship | Un rôle nouveau de la cavéoline dans le transport de la sphingomyéline à la membrane plasmique | en_US |
| dc.language.iso | EN | en_US |
| dc.subject.en | caveolae | |
| dc.subject.en | cardiac myocytes | |
| dc.subject.en | sensitivity and specificity | |
| dc.title.en | CAVIN1-Mediated hERG Dynamics: A Novel Mechanism Underlying the Interindividual Variability in Drug-Induced Long QT | |
| dc.title.alternative | Circulation | en_US |
| dc.type | Article de revue | en_US |
| dc.identifier.doi | 10.1161/CIRCULATIONAHA.123.063917 | en_US |
| dc.subject.hal | Sciences du Vivant [q-bio]/Santé publique et épidémiologie | en_US |
| dc.identifier.pubmed | 38682330 | en_US |
| bordeaux.journal | Circulation | en_US |
| bordeaux.hal.laboratories | Bordeaux Population Health Research Center (BPH) - UMR 1219 | en_US |
| bordeaux.institution | Université de Bordeaux | en_US |
| bordeaux.institution | INSERM | en_US |
| bordeaux.team | ELEANOR_BPH | en_US |
| bordeaux.peerReviewed | oui | en_US |
| bordeaux.inpress | non | en_US |
| bordeaux.import.source | hal | |
| hal.identifier | pasteur-04596797 | |
| hal.version | 1 | |
| hal.popular | non | en_US |
| hal.audience | Internationale | en_US |
| hal.export | false | |
| workflow.import.source | hal | |
| dc.rights.cc | Pas de Licence CC | en_US |
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