Normalization of the calcineurin pathway underlies the regression of hypertensive hypertrophy induced by Na<sup>+</sup>/H<sup>+</sup>exchanger-1 (NHE-1) inhibitionThis paper is one of a selection of papers published in this Special Issue, entitled The Cellular and Molecular Basis of Cardiovascular Dysfunction, Dhalla 70th Birthday Tribute.
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Bibliographic record
Abstract
Na+/H+ exchanger-1 (NHE-1) inhibition induces cardiac hypertrophy regression and (or) prevention in several experimental models, although the intracellular events involved remain unclarified. We aimed to determine whether the calcineurin/NFAT pathway mediates this effect of NHE-1 inhibitors. Spontaneously hypertensive rats (SHR) with cardiac hypertrophy were treated with the NHE-1 inhibitors cariporide and BIIB723 for 30 days. Wistar rats served as normotensive controls. Their hearts were studied by echocardiography, immunoblotting, and real-time RT-PCR. Cytoplasmic Ca2+ and calcineurin Abeta expression were measured in cultured neonatal rat ventricular myocytes (NRVM) stimulated with endothelin-1 for 24 h. NHE-1 blockade induced cardiac hypertrophy regression (heart mass/body mass=3.63+/-0.07 vs. 3.06+/-0.05 and 3.02+/-0.13 for untreated vs. cariporide- and BIIB723-treated SHR, respectively; p<0.05) and decreased myocardial brain natriuretic peptide, calcineurin Abeta, and nuclear NFAT expressions. Echocardiographic evaluation demonstrated a reduction in left ventricular wall thickness without changes in cavity dimensions or a significant decrease in blood pressure. NHE-1-inhibitor treatment did not affect myocardial stiffness or endocardial shortening, but increased mid-wall shortening, suggesting that a positive inotropic effect develops after hypertrophy regression. Cariporide normalized the increased diastolic Ca2+ and calcineurin Abeta expression observed in ET-1-stimulated NRVM. In conclusion, our data suggest that inactivation of calcineurin/NFAT pathway may underlie the regression of cardiac hyper-trophy induced by NHE-1 inhibition.
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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 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.002 | 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 it