Sepsis-induced myocardial depression is associated with transcriptional changes in energy metabolism and contractile related genes: A physiological and gene expression-based approach*
Bibliographic record
Abstract
BACKGROUND: Increased nitric oxide production and altered mitochondrial function have been implicated in sepsis-induced cardiac dysfunction. The molecular mechanisms underlying myocardial depression in sepsis and the contribution of nitric oxide in this process however, are incompletely understood. OBJECTIVES: To assess the transcriptional profile associated with sepsis-induced myocardial depression in a clinically relevant mouse model, and specifically test the hypothesis that critical transcriptional changes are inducible nitric oxide synthase-dependent. DESIGN: Laboratory investigation. SETTING: University affiliated research laboratory. SUBJECTS: C57/BL6 wild type and congenic B6 129P2-Nos2tm1Lau/J (iNOS) mice. INTERVENTIONS: Assessment of myocardial function after 48 hrs of induction of polymicrobial sepsis by caecal ligation and perforation. MEASUREMENTS AND RESULTS: We compared the myocardial transcriptional profile in C57/BL6 wild type mice and congenic B6 129P2-Nos2tm1Lau/J litter mates after 48 hrs of polymicrobial sepsis induced by caecal ligation and perforation. Profiling of 22,690 expressed sequence tags by gene set enrichment analysis demonstrated that inducible nitric oxide synthase -/- failed to down regulate critical bioenergy and metabolism related genes including the gene for peroxisome proliferator-activated receptor gamma coactivator 1. Bioinformatics analysis identified a striking concordance in down regulation of transcriptional activity of proliferator-activated receptor gamma coactivator 1-related transcription factors resulting in sepsis associated myocardial remodeling as shown by isoform switching in the expression of contractile protein myosin heavy chain. In inducible nitric oxide synthase -/- deficient mice, contractile depression was minimal, and the transcriptional switch was absent. CONCLUSIONS: Metabolic and myosin isoform gene expression switch in sepsis-induced myocardial depression is inducible nitric oxide synthase-dependent. Furthermore, we suggest that the molecular switch favoring the expression of fetal isoforms of contraction related proteins is associated with regulation of proliferator-activated receptor gamma coactivator 1 and related transcription factors in an inducible nitric oxide synthase-dependent manner.
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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 | 0.001 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 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".