Abstract 352: MicroRNAs Play A Crucial Role In The Induction Of Endothelial-to-Mesenchymal Transition-Mediated Cardiac Fibrosis.
Bibliographic record
Abstract
Introduction: Fibroblast-like cells derived from aberrant activation of endothelial-to-mesenchymal transition (EndMT) are an important contributor to cardiac fibrosis. TGF-beta signaling plays a pivotal role in the induction of EndMT and cardiac fibrosis. Our recent studies have shown that specific miRNAs are differentially regulated during TGF-beta-induced EndMT and blocking TGF-beta-receptor I (TbetaR1) kinase inhibits TGF-beta-induced EndMT. Hypothesis: We hypothesize that miRNAs that promote EndMT will potentially exacerbate cardiac fibrosis, and knockdown of these miRNAs will attenuate EndMT-mediated cardiac fibrosis. Results and Methods: We investigated the levels of miRNAs and profibrotic markers in the failing human myocardium compared to healthy human heart tissue. Our results indicate that miRNAs upregulated during EndMT were significantly elevated in the failing human myocardium. In addition, failing human myocardium exhibited significant upregulation of profibrotic markers including alpha-SMA, Col1 and PAI-1. Next, primary cultures of mouse cardiac endothelial cells treated with TGF-beta or SB431542 (TbetaR1 kinase inhibitor) were evaluated for EndMT markers using bright field microscopy, fluorescence microscopy, western blot analysis and qRT PCR. We observed that blocking TbetaR1 kinase by SB431542 inhibits specific miRNAs which were upregulated during TGF-beta-induced EndMT. In addition, in silico analysis revealed that these miRNAs target key TGF-beta effectors, which was further confirmed by western blot analysis. Furthermore, overexpression of specific miRNAs using mimics resulted in the induction of EndMT. Next, miRNA mimics in combination with TGF-beta substantially potentiated TGF-beta-induced EndMT. Finally, knockdown of these miRNAs using inhibitors or Cy3-tagged antagomiRs significantly attenuated TGF-beta-induced cardiac EndMT. Conclusions: Our results indicate that TbetaR1 kinase-induced expression of miRNAs is involved in cardiac EndMT. Thus, miRNAs may promote profibrotic signaling in EndMT-derived fibroblast-like cells, which may contribute to fibrogenesis in the human heart.
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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 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 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 | 0.000 |
| 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".