http://purl.uniprot.org/citations/37099628 | http://www.w3.org/1999/02/22-rdf-syntax-ns#type | http://purl.uniprot.org/core/Journal_Citation |
http://purl.uniprot.org/citations/37099628 | http://www.w3.org/2000/01/rdf-schema#comment | "AimsCurrent long QT syndrome (LQTS) therapy, largely based on beta-blockade, does not prevent arrhythmias in all patients; therefore, novel therapies are warranted. Pharmacological inhibition of the serum/glucocorticoid-regulated kinase 1 (SGK1-Inh) has been shown to shorten action potential duration (APD) in LQTS type 3. We aimed to investigate whether SGK1-Inh could similarly shorten APD in LQTS types 1 and 2.Methods and resultsHuman-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) and hiPSC-cardiac cell sheets (CCS) were obtained from LQT1 and LQT2 patients; CMs were isolated from transgenic LQT1, LQT2, and wild-type (WT) rabbits. Serum/glucocorticoid-regulated kinase 1 inhibition effects (300 nM-10 µM) on field potential durations (FPD) were investigated in hiPSC-CMs with multielectrode arrays; optical mapping was performed in LQT2 CCS. Whole-cell and perforated patch clamp recordings were performed in isolated LQT1, LQT2, and WT rabbit CMs to investigate SGK1-Inh (3 µM) effects on APD. In all LQT2 models across different species (hiPSC-CMs, hiPSC-CCS, and rabbit CMs) and independent of the disease-causing variant (KCNH2-p.A561V/p.A614V/p.G628S/IVS9-28A/G), SGK1-Inh dose-dependently shortened FPD/APD at 0.3-10 µM (by 20-32%/25-30%/44-45%). Importantly, in LQT2 rabbit CMs, 3 µM SGK1-Inh normalized APD to its WT value. A significant FPD shortening was observed in KCNQ1-p.R594Q hiPSC-CMs at 1/3/10 µM (by 19/26/35%) and in KCNQ1-p.A341V hiPSC-CMs at 10 µM (by 29%). No SGK1-Inh-induced FPD/APD shortening effect was observed in LQT1 KCNQ1-p.A341V hiPSC-CMs or KCNQ1-p.Y315S rabbit CMs at 0.3-3 µM.ConclusionA robust SGK1-Inh-induced APD shortening was observed across different LQT2 models, species, and genetic variants but less consistently in LQT1 models. This suggests a genotype- and variant-specific beneficial effect of this novel therapeutic approach in LQTS."xsd:string |
http://purl.uniprot.org/citations/37099628 | http://purl.org/dc/terms/identifier | "doi:10.1093/europace/euad094"xsd:string |
http://purl.uniprot.org/citations/37099628 | http://purl.uniprot.org/core/author | "Das S."xsd:string |
http://purl.uniprot.org/citations/37099628 | http://purl.uniprot.org/core/author | "Mura M."xsd:string |
http://purl.uniprot.org/citations/37099628 | http://purl.uniprot.org/core/author | "Schwartz P.J."xsd:string |
http://purl.uniprot.org/citations/37099628 | http://purl.uniprot.org/core/author | "Crotti L."xsd:string |
http://purl.uniprot.org/citations/37099628 | http://purl.uniprot.org/core/author | "Gnecchi M."xsd:string |
http://purl.uniprot.org/citations/37099628 | http://purl.uniprot.org/core/author | "Sala L."xsd:string |
http://purl.uniprot.org/citations/37099628 | http://purl.uniprot.org/core/author | "Zaza A."xsd:string |
http://purl.uniprot.org/citations/37099628 | http://purl.uniprot.org/core/author | "Koren G."xsd:string |
http://purl.uniprot.org/citations/37099628 | http://purl.uniprot.org/core/author | "Barbieri M."xsd:string |
http://purl.uniprot.org/citations/37099628 | http://purl.uniprot.org/core/author | "Wilde A.A.M."xsd:string |
http://purl.uniprot.org/citations/37099628 | http://purl.uniprot.org/core/author | "Brink P."xsd:string |
http://purl.uniprot.org/citations/37099628 | http://purl.uniprot.org/core/author | "Srinivasan D."xsd:string |
http://purl.uniprot.org/citations/37099628 | http://purl.uniprot.org/core/author | "Remme C.A."xsd:string |
http://purl.uniprot.org/citations/37099628 | http://purl.uniprot.org/core/author | "Casini S."xsd:string |
http://purl.uniprot.org/citations/37099628 | http://purl.uniprot.org/core/author | "Odening K.E."xsd:string |
http://purl.uniprot.org/citations/37099628 | http://purl.uniprot.org/core/author | "Zehender M."xsd:string |
http://purl.uniprot.org/citations/37099628 | http://purl.uniprot.org/core/author | "Gepstein L."xsd:string |
http://purl.uniprot.org/citations/37099628 | http://purl.uniprot.org/core/author | "Louradour J."xsd:string |
http://purl.uniprot.org/citations/37099628 | http://purl.uniprot.org/core/author | "Giannetti F."xsd:string |
http://purl.uniprot.org/citations/37099628 | http://purl.uniprot.org/core/author | "Alerni N."xsd:string |
http://purl.uniprot.org/citations/37099628 | http://purl.uniprot.org/core/author | "Nimani S."xsd:string |
http://purl.uniprot.org/citations/37099628 | http://purl.uniprot.org/core/author | "Pradhananga S."xsd:string |