Abstract 12433: miR 187a-3p Prevents Septic-Induced Myocardial Dysfunction by Targeting the Inflammatory Cytokines TNFa and IL-6
Bibliographic record
Abstract
Introduction: Patients with severe, sepsis can develop acute heart failure characterized by left ventricular dilatation and decreased contractility. Inflammatory mediators, including TNFα, IL-6 and IL-1β contribute to the activation of inflammation and ventricular remodeling. Therapeutic interventions for sepsis are lacking. Previously, we demonstrated that miR187-3p, a regulator of TNFα is dysregulated in the septic heart, in a pre-clinical model of sepsis. Hypothesis: We hypothesize that administering miR187-3p mimic would reduce inflammatory cytokine production and improve cardiac function and mortality rate. Methods: Polymicrobial sepsis was induced in mice via cecal ligation and perforation (CLP) surgery, mice undergoing sham surgery served as controls. MiR187-3p mimic, miRNA negative control, or saline were administered IV 6 hrs post-CLP. At 48 hrs post-CLP, following echocardiographic and hemodynamic assessments, the mice were sacrificed, and the hearts collected for biochemical, and molecular analysis. To complement the experimental findings, autopsy human hearts and circulatory blood samples from septic patients and healthy controls were collected and the expression of miR187a-3p and inflammatory cytokines were analyzed. Results: Administration of miR-187-3p mimic to septic mice 6 hrs post-CLP increased survival, improved echo-derived indices of cardiac function (left ventricular ejection fraction, fractional shortening), increased bacterial clearance and reduced inflammation when compared to septic mice receiving a scrambled control miR. In septic mice, miR-187-3p expression decreased in both the circulation and heart tissue. In addition to TNFα, bioinformatic analysis, confirmed by luciferase assays, identified IL-6 as a specific target of miR187-3p in cardiac myocytes. In septic patients, the expression of miR-187-3p and target inflammatory cytokines decreased in plasma and autopsied hearts. Conclusions: Delivery of miR-187-3p improves outcomes in sepsis-induced myocardial dysfunction. Thus, miR-187-3p serves as a potential biomarker and therapeutic target for prevention and prognostic reflection in sepsis-induced myocardial dysfunction.
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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) | 0.000 | 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".