Role of neuronal nitric oxide synthase in lipopolysaccharide-induced tumor necrosis factor-alpha expression in neonatal mouse cardiomyocytes
Bibliographic record
Abstract
OBJECTIVE: Neuronal nitric oxide synthase (nNOS) has been shown to regulate intracellular calcium in cardiomyocytes. Calcium in turn modulates extracellular signal-related kinase (ERK) signaling, which is important in tumor necrosis factor-alpha (TNF-alpha) expression during lipopolysaccharide (LPS) stimulation. However, the role of nNOS in LPS-induced TNF-alpha expression is not known. We hypothesized that nNOS suppresses LPS-induced TNF-alpha expression by inhibiting the calcium/ERK signaling pathway. METHODS AND RESULTS: Cultured neonatal mouse cardiomyocytes were challenged with LPS for 4 h. While there was no change in the basal Ca(2+) concentration, LPS increased peak Ca(2+) levels. LPS stimulation increased TNF-alpha mRNA and protein levels in wild-type cells however, the responses were enhanced in nNOS(-/-) cardiomyocytes. Treatment with an antisense oligonucleotide against nNOS also significantly enhanced TNF-alpha expression during LPS stimulation. Furthermore, LPS-induced ERK phosphorylation was significantly increased in the nNOS(-/-) compared to wild-type cardiomyocytes. The enhanced TNF-alpha expression in nNOS(-/-) cardiomyocytes was abrogated by an L-type calcium channel blocker verapamil or ERK1 siRNA. Finally, myocardial ERK phosphorylation and TNF-alpha expression were increased while cardiac function was decreased in endotoxemia in nNOS(-/-) compared to wild-type mice. CONCLUSIONS: nNOS inhibits LPS-induced TNF-alpha expression in cardiomyocytes and improves cardiac function in endotoxemia. The inhibitory role of nNOS is mediated by a reduction in L-type calcium channel-dependent ERK signaling in cardiomyocytes.
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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 | 0.005 | 0.001 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.001 |
| Bibliometrics | 0.002 | 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".