{"doi":"10.14814/phy2.15696","title":"Inhibition of Wnt/β‐catenin signaling upregulates Na<sub>v</sub>1.5 channels in Brugada syndrome <scp>iPSC</scp>‐derived cardiomyocytes","abstract":"Abstract The voltage‐gated Na v 1.5 channels mediate the fast Na + current ( I Na ) in cardiomyocytes initiating action potentials and cardiac contraction. Downregulation of I Na , as occurs in Brugada syndrome (BrS), causes ventricular arrhythmias. The present study investigated whether the Wnt/β‐catenin signaling regulates Na v 1.5 in human‐induced pluripotent stem cell‐derived cardiomyocytes (iPSC‐CMs). In healthy male and female iPSC‐CMs, activation of Wnt/β‐catenin signaling by CHIR‐99021 reduced ( p &lt; 0.01) both Na v 1.5 protein and SCN5A mRNA. In iPSC‐CMs from a BrS patient, both Na v 1.5 protein and peak I Na were reduced compared to those in healthy iPSC‐CMs. Treatment of BrS iPSC‐CMs with Wnt‐C59, a small‐molecule Wnt inhibitor, led to a 2.1‐fold increase in Na v 1.5 protein ( p = 0.0005) but surprisingly did not affect SCN5A mRNA ( p = 0.146). Similarly, inhibition of Wnt signaling using shRNA‐mediated β‐catenin knockdown in BrS iPSC‐CMs led to a 4.0‐fold increase in Na v 1.5, which was associated with a 4.9‐fold increase in peak I Na but only a 2.1‐fold increase in SCN5A mRNA. The upregulation of Na v 1.5 by β‐catenin knockdown was verified in iPSC‐CMs from a second BrS patient. This study demonstrated that Wnt/β‐catenin signaling inhibits Na v 1.5 expression in both male and female human iPSC‐CMs, and inhibition of Wnt/β‐catenin signaling upregulates Na v 1.5 in BrS iPSC‐CMs through both transcriptional and posttranscriptional mechanisms.","journal":"Physiological Reports","year":2023,"id":380882,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":4,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9545,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1146163,"name":"Ruonan Gu","orcid":"0000-0002-5007-3836","position":1,"is_corresponding":false},{"id":1146483,"name":"Cencen Chu","orcid":null,"position":2,"is_corresponding":false},{"id":1146164,"name":"Ying Xia","orcid":"0000-0002-0126-6594","position":3,"is_corresponding":false},{"id":676680,"name":"Jerry Wang","orcid":"0000-0002-9746-1211","position":4,"is_corresponding":false},{"id":1146165,"name":"Darryl R. Davis","orcid":"0000-0001-9642-3910","position":5,"is_corresponding":false},{"id":1146166,"name":"Wenbin Liang","orcid":"0000-0002-7272-9920","position":6,"is_corresponding":false},{"id":1146162,"name":"Aizhu Lu","orcid":"0000-0002-4116-148X","position":0,"is_corresponding":true}],"reference_count":63,"raw_metadata":null,"created_at":"2026-07-19T01:17:04.905707Z","pmid":"37226398","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}