Abstract 11961: Ductus Arteriosus Oxygen Response is Mediated by Mitochondrial Subunit NDUFS2
Bibliographic record
Abstract
Introduction: The ductus arteriosus (DA) is a fetal vessel connecting the pulmonary artery (PA) and aorta, diverting oxygenated blood away from the developing lungs to the systemic circulation. The DA rapidly constricts in response to the increase in arterial oxygen (O 2 ) following the first breath. Failure of the DA to close in response to O 2 results in persistent ductus arteriosus, one of the most common complications of preterm birth. Mitochondria are known to play an important role in the O 2 response of DA smooth muscle cells (DASMC), however the mechanism is not fully understood. A subunit of mitochondrial Complex I, NDUFS2 (NADH:ubiquinone oxidoreductase core subunit 2) mediates the O 2 response of other specialized O 2 sensing tissues (PA and carotid body); we assess whether NDUFS2 also plays a role in DA O 2 sensing. Methods: DASMC were isolated from male term (29 days gestation) fetal New Zealand white rabbits. Cell lines were purified via fluorescence activated cell sorting, excluding CD90 + and CD31 + cells (fibroblasts and endothelial cells, respectively). Smooth muscle cell purity was confirmed using flow cytometry for α-smooth muscle actin (α-SMA). Primary cultures were 97.65% ± 0.65% CD90 - CD31 - , and were 100% α-SMA + post-sorting. We measured the O 2 responsiveness of DASMC using confocal microscopy, measuring changes in intracellular calcium with Cal-520AM. Cells were cultured in hypoxia (2.5% O 2 , pO 2 = 41 mmHg), with O 2 -induced increase in calcium relative to hypoxic baseline serving as a surrogate for constriction. DASMC were treated for 48 hours with 30 pmol siRNA and 90 pmol Lipofectamine® RNAiMAX to knockdown gene expression of NDUFS2 or a negative control. Knockdown was confirmed using qPCR. Results & Conclusions: There was a 14.7% (±2.6%, n=33, p<0.0001) increase in intracellular calcium relative to hypoxic baseline in siNC-treated cells. O 2 response was obliterated when treated with siNDUFS2 (0.7% ± 2.1%, n=29, p=0.798), with a 90.9% ± 1.89% knockdown of NDUFS2 mRNA expression. These data suggest a critical role for the mitochondrial electron transport chain, specifically NDUFS2, in DA oxygen responsiveness. While further functional studies will be required, our findings suggest a novel potential therapeutic target to modulate DA patency.
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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 | 0.000 |
| 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) | 0.003 | 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".