Abstract 19446: Role of miR-181 Family in the Heart: A Tale of Two Intracellular Compartments
Bibliographic record
Abstract
Recent reports suggest that mi(cro)RNAs, non-coding RNAs, can regulate numerous human genes. miRNAs play an important role in physiologic and pathologic processes of cardiovascular health. We identified a nuclear encoded miRNA (miR-181c) that translocates into mitochondria to regulate a mitochondrial gene, and ultimately affects mitochondrial function. To investigate how miR-181c leads to cardiac injury, we designed miR-181-sponges, RNA molecules with ten repeated complimentary miR-181 “seed” sequences, and generated a set of stable-H9c2 cells by transfecting either a scrambled- or the miR-181-sponge-sequences. Sponge-H9c2 showed a significant decrease in ROS production and reduced basal mitochondrial respiration, and significant protection against Doxorubicin-induced oxidative stress. However, chronic down-regulation of the entire miR-181 family also stimulates PTEN expression, and thus the sponge decreased PI3K signaling. Thus, protection against Doxorubicin is enhanced when we treated sponge-H9c2 with siRNA against PTEN. We hypothesize that miR-181a/b targets PTEN in the cytosol and miR-181c targets mt-COX1 in the mitochondria. To extend this finding, miR-181a/b-/- and miR-181c/d-/- mice were used. miR-181a/b-/- shows a significant decrease in cardiac function at baseline compared to both miR-181c/d-/- and WT groups. Basal mitochondrial ROS production was significantly decreased in miR-181c/d-/- compare to WT or miR-181a/b-/-. Using both Electron Microscopy and light-scattering at 540 nm by isolated heart mitochondria, we found that the mitochondria are smaller in the miR-181c/d-/- , and genomic DNA-qPCR showed the number of mitochondria was markedly higher in the miR-181c/d-/- heart compared to the WT or 181a/b-/- groups. miR-181c/d-/- showed a significant decrease, while miR-181a/b-/- showed a significant increase in infarct size compared to WT, when the hearts were challenged with ischemia-reperfusion injury. Taken together, the miR-181 family regulates important signaling pathways in oxidative stress, notably with detrimental results by targeting mt-COX1 (miR-181c), or with protection by targeting PTEN (miR-181a/b).
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.001 | 0.001 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.006 | 0.003 |
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 source (direct Gemma or distilled Codex), 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".