Abstract 13694: Hsf1 Attenuates Pressure Overload Induced-cardiac Fibrosis via Inhibiting Smad3 Phosphorylation and Nuclear Translocation
Bibliographic record
Abstract
Introduction: Heat shock transcription factor 1 (HSF1) is an intrinsic cardioprotective factor against cardiac hypertrophy. However, little is known about the role of HSF1 in cardiac fibrosis. Here we hypothesize that HSF1 reverses pressure overload induced-cardiac fibrosis via inhibiting Smad3 phosphorylation and nuclear translocation. Methods: Human tissue samples were collected from the left ventricles of dilated cardiomyopathy patients undergoing heart transplant and normal heart donors for control and were interrogated via western blot and realtime-PCR. A HSF1 transgenic (TG) mouse was generated. Transverse aortic constriction (TAC) was performed with wild type (WT) mice as control and cardiac structure and function were measured by echocardiography and pathological test. Cardiomyocytes (CMs) isolated from neonatal mice were imposed with mechanical stretch (MS) in vitro. Results: HSF1 phosphorylation at Ser230 was significantly decreased in failing hearts (55% vs normal hearts) characterized with significant cardiac fibrosis manifested with increased expression of collagen III and connective tissue growth factor (CTGF) . WT mice and TG mice were subjected to TAC. After 4 weeks of TAC, WT mice developed a remarkable maladaptive hypertrophy and cardiac fibrosis in comparison to WT mice. TG mice exhibited a smaller LV end-diastolic diameter (LVEDD), higher ejection fraction (EF), decreased LV weight/tibial length (LW/TL) and CMs cross sectional area (CSA), less interstitial and perivascular fibrosis, as well as preserved expression of collagen III and CTGF compared to WT mice. TG mouse hearts also showed reduced phosphorylation and nuclear translocation of Smad3 than WT mice. MS was found to significantly inhibit HSF1 phosphorylation, but promoted the Smad3 phosphorylation and nuclear translocation in CMs. Co-Immunoprecipitation showed that HSF1 directly binds Smad3 in CMs in vitro, which was decrease by MS or treatment with KNK437 (HSF1 inhibitor). TG mice demonstrate more of HSF1 and Smad3 binding and less phosphorylation and nuclear translocation of Smad3 compared to WT mice after TAC. Conclusion: HSF1 attenuates pressure overload induced-cardiac fibrosis by inhibiting Smad3 phosphorylation and nuclear translocation.
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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 | 0.000 | 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 | 0.000 |
| 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".