Abstract 374: FGF2 Isoform-selective as well as Non-selective Signals Protect Cardiomyocytes from Doxorubicin-induced Cell Death
Bibliographic record
Abstract
Introduction: Doxorubicin (DOX) induced cardiotoxicity, including cardiomyocyte cell death, remains a major challenge for anticancer therapies. DOX can disrupt the balance between synthesis and degradation systems by affecting major cellular signaling pathways including the mammalian target of Rapamycin (mTOR), and AMP-activated kinase (AMPK). Fibroblast Growth Factor 2 (FGF2), a multifunctional protein expressed by heart cells and downregulated by DOX, consists of two types of isoforms, low molecular weight, Lo-FGF2, (~18 kDa) and high molecular weight, Hi-FGF2, (>20 kDa), displaying isoform-selective and non-selective properties. We have studied the effects of added FGF2 isoforms on DOX induced dysregulation of signaling pathways impacting on cardiomyocyte survival and autophagy. Methods and Results: Primary cultures of neonatal rat cardiomyocytes were subjected to 0.5 μM DOX in the absence or presence of pretreatment with FGF2 isoforms, at 10 ng/ml. Both Hi- and Lo- FGF2 decreased DOX-induced injury and cell death, measured by LDH release, a Live-Dead assay, and activation of caspase 3. Neither isoform prevented the DOX-induced cell death in MCF7 cells, a breast cancer cell line. In myocytes, both isoforms prevented the DOX-induced downregulation of mTORC1 activity (phospho-Ser2448). The mTOR inhibitor Rapamycin prevented the beneficial effects of FGF2. Hi-FGF2, but not Lo-FGF2, significantly increased AMPK activity (phospho-Thr172) pre- and post-DOX. Compound C, an inhibitor of AMPK, prevented the protective effect of Hi- , but not Lo-, FGF2. To assess autophagy, cardiomyocytes were transduced with an adenoviral vector for GFP-LC3. Numbers of GFP-LC3 aggregates (dots) per cell were measured, and suggested that both Hi- and Lo-FGF2 prevented the DOX-induced increases in autophagy and autophagy flux, as also indicated by increased levels of p62 post-DOX in the presence of FGF2. Pharmacological inhibition of autophagy by 3-Methyladenine was protective against DOX. Conclusions: FGF2 isoforms protect cardiomyocytes against acute DOX damage, by activating mTORC1 (both Hi or Lo FGF2), as well as, in the case of Hi-FGF2, the AMPK pathway. Protection by FGF2 isoforms was associated with prevention of accelerated flux.
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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) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.001 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.001 | 0.000 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.001 | 0.003 |
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".