Determining the protective role of prostaglandin signalling in the hypoxia-exposed neonatal heart
Bibliographic record
Abstract
Systemic hypoxia affects more than 9 million infants around the world each year and directly contributes to increased morbidity and mortality in early life. While a lack of oxygen at the tissue level results in a number of conditions known as diseases of prematurity, the developing heart appears to be particularly vulnerable. At the cellular level, reduced oxygen tension promotes the hypoxia-inducible factor (HIF) adaptive response, altering cardiac metabolism and elevating the expression of the pro-death Bcl-2 protein, Bnip3. While initially adaptive, emerging evidence suggests that these specific components of the HIF-1 response are detrimental to cardiac structure and function, which impairs downstream tissue perfusion, further worsening disease progression. Because of this, development of potential pharmacological approaches to treat the maladaptive effects of HIF-activation could be therapeutic. Previous evidence from our lab and others has suggested that prostaglandins, locally produced lipid signalling molecules, are protective during hypoxic pathologies, but the mechanism remains unclear. Therefore, we chose to investigate if and how misoprostol, an FDA- and Health Canada-approved prostaglandin E1 analogue, may protect the neonatal heart. This thesis summarizes our findings across three independent studies. In the first study we characterized the molecular mechanism by which misoprostol treatment represses Bnip3 protein expression in the neonatal rat heart, while also showing that it directs the alternative splicing of Bnip3 to produce a smaller isoform, called sNip. Through this study we found that sNip not only opposes Bnip3 activity but promotes cardiomyocyte maturation through nuclear calcium signalling. This novel mechanism led to our second study where we used misoprostol to promote the expression of sNip in order to oppose an aberrant hypoxia-induced proliferative phenotype observed in neonatal cardiomyocytes. The third study examines how misoprostol activates a pathway independent of repression and alternative splicing, directly targeting and inhibiting Bnip3’s deleterious activity at the mitochondria and endoplasmic reticulum through phosphorylation. Together these findings represent a major advancement in our understanding of Bnip3 in the neonatal heart, by demonstrating for the first time that its expression and activity can be pharmacologically modulated using misoprostol. Ongoing investigation of misoprostol’s long term protective effects on cardiac structure and function are required, as we continue to try and find ways to reduce the burden of hypoxia in early life for this vulnerable population.
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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) | 0.000 | 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".