Endothelial nitric oxide synthase promotes neonatal cardiomyocyte proliferation by inhibiting tissue inhibitor of metalloproteinase-3 expression
Bibliographic record
Abstract
OBJECTIVE: We have recently demonstrated that endothelial nitric oxide synthase (eNOS) promotes cardiomyocyte proliferation. However, mechanisms by which eNOS regulates cardiomyocyte proliferation are not fully understood. The goal of the present study was to investigate the role of tissue inhibitor of metalloproteinase-3 (TIMP-3) in eNOS-mediated cardiomyocyte proliferation. METHODS AND RESULTS: Experiments were conducted in cultured neonatal mouse cardiomyocytes. TIMP-3 expression was significantly decreased in wild-type (WT) cardiomyocytes treated with an adenoviral eNOS (Ad-eNOS). Furthermore, TIMP-3 levels were significantly decreased in cardiomyocytes derived from eNOS transgenic mice. Conversely, TIMP-3 transcript levels were significantly elevated in eNOS(-/-) cardiomyocytes. The inhibitory effect of NO on TIMP-3 expression was dependent on S-nitrosylation of c-jun, a subunit of AP-1. Cell proliferation was increased in TIMP-3(-/-) cardiomyocytes while recombinant TIMP-3 decreased proliferation in both TIMP-3(-/-) and WT cardiomyocytes. Furthermore, the decline in proliferation observed in eNOS(-/-) cardiomyocytes was abrogated when TIMP-3 expression was blocked by an anti-TIMP-3 antibody. In vivo cardiomyocyte proliferation was assessed by Ki67 immunostaining on postnatal day 1 hearts. Ki67-positive cardiomyocytes were decreased in eNOS(-/-), but increased in eNOS-Tg and TIMP-3(-/-) hearts compared to WT controls. CONCLUSIONS: Our study suggests that eNOS promotes neonatal cardiomyocyte proliferation by inhibiting TIMP-3 expression.
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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 | 0.009 | 0.001 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.001 |
| Bibliometrics | 0.001 | 0.001 |
| 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) | 0.000 | 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".