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 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) | 0.001 | 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) | 0.006 | 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".