Abstract 031: β-Adrenergic Receptor-Mediated Transactivation Of Epidermal Growth Factor Receptor Decreases Cardiomyocyte Apoptosis Through Differential Activation Of ERK1/2 and Akt
Bibliographic record
Abstract
β-adrenergic receptors (βAR) are critical regulators of cardiac function whose dysregulation during heart failure are associated with diminished function. However, βAR-mediated EGFR transactivation has been shown to relay cardioprotection in a mouse model of heart failure via unknown mechanisms. We hypothesized that transactivation of EGFR promotes survival via distinct cardiomyocyte signaling responses leading to decreases in apoptosis. To test this hypothesis, C57BL/6 mice were injected with isoproterenol (Iso) in the presence or absence of the EGFR antagonist AG1478 and ERK1/2 and Akt phosphorylation and subcellular distribution were assessed. Following 10 min Iso stimulation, increases in ERK1/2 and Akt phosphorylation were observed in cytosolic, plasma membrane and nuclear fractions. Phosphorylation of ERK1/2 were AG1478 sensitive in all three fractions while Akt phosphorylation occurred through EGFR-transactivation only in plasma membrane and nuclear fractions, which was confirmed in rat neonatal cardiomyocytes (RNCM). Additionally, EGFR-transactivation by βAR decreased apoptosis, as measured via caspase 3 activation/activity and TUNEL assay, which was sensitive to inhibition of both ERK1/2 and Akt signaling pathways. Increased phosphorylation of ERK1/2 and Akt in the nucleus and the ability to inhibit Iso-mediated changes in apoptosis with the transcriptional inhibitor Actinomycin D suggested that the cardioprotective effects of Iso-mediated EGFR transactivation may be influenced by changes in gene transcription. An Apoptotsis RT2 PCR Array was used to identify changes in transcript levels of 84 apoptotic genes. Of these, 12 were found to be altered in response to EGFR inhibition in the presence of Iso. These results demonstrate that βAR-mediated EGFR transactivation in the heart induces differential subcellular activation of ERK1/2 and Akt and leads to the promotion of cell survival, in part through the modulation of apoptotic gene expression in cardiomyocytes. Further understanding the downstream consequences of these effects in response to βAR-mediated EGFR transactivation could lead to improved therapies for the treatment of heart failure.
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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) | 0.001 | 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".