Abstract 111: Wnt Signaling Inhibition Rescues Voltage-Gated Na + Current in Brugada Syndrome Patient Cardiomyocytes
| Autor: | Jerry Wang, Cencen Chu, Wenbin Liang, Aizhu Lu |
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| Rok vydání: | 2019 |
| Předmět: | |
| Zdroj: | Circulation Research. 125 |
| ISSN: | 1524-4571 0009-7330 |
| DOI: | 10.1161/res.125.suppl_1.111 |
| Popis: | Aims: Both inherited arrhythmogenic diseases (such as Brugada Syndrome) and heart failure are associated with reduced voltage-gated Na + current (I Na ) which promotes lethal arrhythmias and sudden deaths. We and others have shown that Wnt/β-catenin signaling (Wnt signaling), which is active in heart disease, inhibits I Na in rat and mouse cardiomyocytes. But whether Wnt signaling regulates I Na in human cardiomyocytes and represents a novel therapeutic target is unknown. This study aims to investigate if Wnt signaling inhibits I Na in human cardiomyocytes, to elucidate the underlying mechanisms, and to test if blocking Wnt signaling can rescue I Na in Brugada Syndrome patient cardiomyocytes. Methods and Results: Cardiomyocytes were differentiated from human induced pluripotent stem cells (hiPSC-CMs) that were derived from healthy volunteers or a Brugada Syndrome patient. Whole-cell patch-clamp technique was used for I Na measurement. Activation of Wnt signaling in healthy hiPSC-CMs led to a 69% reduction in I Na amplitude (peak current at -20 mV: -10.5±2.8 pA/pF, n=9 cells vs. control -33.6±4.1 pA/pF, n=6 cells, pSCN5A mRNA (encoding the pore-forming α subunit of I Na , Na v 1.5). In addition, Wnt signaling also reduced Na v 1.5 glycosylation causing a depolarizing shift of I Na activation curve (a mechanism found in human, but not in rodent, cardiomyocytes). Blocking Wnt signaling in Brugada hiPSC-CMs with shRNA-mediated β-catenin knockdown led to a 13-fold increase in I Na amplitude (pNa, blocking Wnt signaling also upregulated SCN5A mRNA and Na v 1.5 protein, without affecting expression of other cardiac ion channels in Brugada hiPSC-CMs. Conclusions: This study demonstrated Wnt-inhibition of human cardiac I Na and, using Brugada Syndrome as an example, demonstrated that blocking Wnt signaling is a novel therapeutic strategy to rescue I Na in heart disease. |
| Databáze: | OpenAIRE |
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