β‐adrenergic receptor‐mediated DNA synthesis in neonatal rat cardiac fibroblasts proceeds via a phosphatidylinositol 3‐kinase dependent pathway refractory to the antiproliferative action of cyclic AMP
Bibliographic record
Abstract
The following study was undertaken to elucidate the cytoskeletal phenotype of neonatal rat cardiac fibroblasts (NNCF) and the signaling pathways coupled to beta-adrenergic receptor stimulated DNA synthesis. The cytoskeletal proteins vimentin, and smooth muscle alpha-actin were detected in NNCF, suggestive of a myofibroblast phenotype. Isoproterenol (ISO) treatment stimulated (3)H-thymidine uptake, and concomitantly increased intracellular cyclic AMP levels. However, cyclic AMP-elevating agents markedly decreased DNA synthesis. Coincident with growth, ISO-stimulated phosphatidylinositol 3-kinase (PI3-K) activity, and the PI3-K inhibitor LY294002 abrogated enzyme activity, and DNA synthesis. Unexpectedly, the serine/threonine kinase protein kinase Balpha (PKBalpha), a putative downstream target of PI3-K, was dephosphorylated following ISO treatment. Despite PKBalpha inactivation, the phosphorylation of its putative downstream target, the pro-apoptotic enzyme glycogen synthase kinase-3alpha was significantly increased in response to ISO. These latter effects of ISO were mimicked by the cyclic AMP-elevating agent forskolin. Lastly, ISO treatment increased p70 ribosomal S6 kinase (p70S6K) phosphorylation, as reflected by an upward electrophoretic mobility shift. The pretreatment with rapamycin abrogated the ISO-mediated mobility shift of p70S6K, and DNA synthesis. Collectively, these data demonstrate that NNCF express a myofibroblast phenotype, and beta-adrenergic agonists promote DNA synthesis via a PI3-K-dependent pathway involving p70S6K. Although unable to suppress ISO-stimulated DNA synthesis, cyclic AMP can influence specific downstream targets of PI3-K highlighting a novel crosstalk between these signaling pathways.
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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 | 0.000 |
| 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".