Abstract 17301: Increased Pulmonary Vascular and Systemic Response to Chronic Hypoxia in Sirtuin 1 Mutant Mice: a Role for Hypoxia-inducible Factor-3α?
Bibliographic record
Abstract
Introduction: Pulmonary Hypertension is caused by occlusive remodelling of pulmonary arterioles leading to increased pulmonary vascular resistance, right ventricle hypertrophy and eventually failure. Sirtuin-1 (Sirt1) is an NAD+-dependent deacetylase that has been strongly implicated in endothelium homeostasis in systemic vessels, but little is known about its role in hypoxia sensing. Hypothesis: We assessed the hypothesis that absence of Sirt1 catalytic activity is detrimental to the hypoxic response in mice. Methods: Mice lacking Sirt1 catalytic activity (sirt1Y/Y, H355Y) and their wild type (WT) littermates were exposed to chronic hypoxia (10% O2) for 1, 7 or 21 days. Results: Sirt1Y/Y exhibited an exaggerated increase in right ventricle systolic pressure, apparent within the first week of hypoxic exposure, which progressively increased over the 3 week CH exposure period (42±2 sirt1Y/Y vs. 30±1 WT; n=27/group, p< 0.001). Right ventricular hypertrophy, assessed by the RV/LV+S weight ratio, was also increased (Day 21: 0.56±0.01 sirt1Y/Y vs. 0.43±0.01 WT, n=27/group; p< 0.001). Hemtaocrit levels were similar in Sirt1Y/Y and WT mice at baseline; however, there was a delayed increase after three weeks of CH in Sirt1Y/Y mice relative to WT mice (71±2% sirt1Y/Y vs. 63±1% WT, n=17/group; p<0.001). Plasma levels of erythropoietin (EPO), assessed by ELISA at each time point, were markedly increased at Day 7 in Sirt1Y/Y vs. WT mice (492±240 vs. 81±16pg/mL, respectively; n=7-9, p< 0.05) but normalized at later time points (Day 21: 75±9 sirt1Y/Y vs. 96±12pg/mL WT; n=4/group). Surprisingly, expression of both HIF1α and 2α mRNA was decreased in mutant mice lungs during chronic hypoxia at all time points, as was the expression of several HIF1/2α responsive target genes. However, there was a dramatic increase in HIF3α in Sirt1 mutant vs. WT lungs, which has been implicated both in repression of other HIFs as well as in directly mediating hypoxic signaling. Conclusions: Loss of Sirt-1 deacetylation activity led to an exaggerated pulmonary and systemic response to hypoxia, consistent with a role for Sirt1 in hypoxia sensing and/or signaling. As well, our data suggest that HIF3α is a novel downstream target for Sirt1 in the regulation of the response to chronic hypoxia.
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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) | 0.001 | 0.001 |
| Bibliometrics | 0.001 | 0.000 |
| Science and technology studies | 0.000 | 0.002 |
| Scholarly communication | 0.001 | 0.000 |
| Open science | 0.001 | 0.000 |
| Research integrity | 0.001 | 0.002 |
| Insufficient payload (model declined to judge) | 0.008 | 0.002 |
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".