Reduction of <i>I</i> <sub>to</sub> Causes Hypertrophy in Neonatal Rat Ventricular Myocytes
Bibliographic record
Abstract
Prolonged action potential duration (APD) and decreased transient outward K+ current (I(to)) as a result of decreased expression of K(v4.2) and K(v4.3) genes are commonly observed in heart disease. We found that treatment of cultured neonatal rat ventricular myocytes with Heteropoda Toxin3, a blocker of cardiac I(to), induced hypertrophy as measured using cell membrane capacitance and (3)H-leucine uptake. To dissect the role of specific I(to)-encoding genes in hypertrophy, I(to) was selectively reduced by overexpressing mutant dominant-negative (DN) transgenes. I(to) amplitude was reduced equally (by about 50%) by overexpression of DN K(v1.4) (K(v1.4)N) or DN K(v4.2) (either K(v4.2)N or K(v4.2)W362F), but only DN K(v4.2) prolonged APD duration (at 1 Hz) and induced myocyte hypertrophy. This hypertrophy was prevented by coexpressing wild-type K(v4.2) channels (K(v4.2)F) with the DN K(v4.2) genes, suggesting the hypertrophy is due to I(to) reduction and not nonspecific effects of transgene overexpression. The hypertrophy caused by reductions of K(v4.x)-based I(to) was associated with increased activity of the calcium-dependent phosphatase, calcineurin, and could be prevented by coinfection with Ad-CAIN, a specific calcineurin inhibitor. The hypertrophy and calcineurin activation induced by K(v4.2)N infection were prevented by blocking Ca2+ entry and excitability with verapamil or high [K+]o. Our studies suggest that reductions of K(v4.2/3)-based I(to) play a role in hypertrophy signaling by activation of calcineurin.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.002 | 0.001 |
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 source (direct Gemma or distilled Codex), 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".