Inhibition of Wnt/β‐catenin signaling upregulates Na<sub>v</sub>1.5 channels in Brugada syndrome <scp>iPSC</scp>‐derived cardiomyocytes
Bibliographic record
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 < 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.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.001 | 0.001 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.000 | 0.001 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one teacher head, not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".