Abstract 346: A Novel Interaction Between E2F and β-adrenergic Pathways Regulates Survival and Growth in Murine Myocardium
Bibliographic record
Abstract
The E2F/Pocket protein (Rb) pathway regulates cell growth, differentiation, and death by modulating gene expression. We previously examined this pathway in myocardium via manipulation of E2F6, which represses gene activity independently of Rb. Mice with cardiac specific expression of E2F6 develop dilated cardiomyopathy (DCM) without any signs of hypertrophic growth. We assessed the mechanisms of the apparent failure of compensatory growth as well as their response to the β-adrenergic agonist isoproterenol (iso). E2F6 transgenic (Tg) mice present with left ventricle dilation and significantly reduced ejection fraction as early as 2 weeks which persists into adulthood, but with no apparent increase in left ventricle weight: body weight (LVW:BW). E2F6-Tg mice treated with iso show double the increase in LVW: BW than their Wt counterparts (32% vs 16%, p-value: 0.007). Western blot revealed a specific activation of the β2-adrenergic pathway in Tg myocardium under basal conditions including a ~2-fold increase in β2-adrenergic receptors (β2-AR) (p-value: 8.9E-05), protein kinase A catalytic subunit (PKA-C) (p-value: 0.0176), activated c-SRC tyrosine-protein kinase (p-value: 0.0002), and an induction of the anti-apoptotic gene Bcl2. In contrast, a ~70% decrease in the cardiac growth regulator: AKT1 (p-value 0.0001) and a 4-fold increase in cyclic AMP dependent phosphodiesterase 4D (PDE4D), the negative regulator of PKA activity, was evident in Tg myocardium. The expression of E2F3 was de-regulated by E2F6, but was restored by iso while Rb expression was down-regulated. Thus deregulation of E2F/Rb pathway by E2F6 altered the β-adrenergic signaling pathway such that survival signaling was activated while hypertrophy was repressed resulting in the development of DCM without any increase in muscle mass. These data reveal a novel interplay between E2F and the β adrenergic pathway which regulate cardiac growth and fate.
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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 | 0.001 |
| Insufficient payload (model declined to judge) | 0.003 | 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".