Role of Hypoxia‐Inducible‐Factor‐2α in Transcriptional Regulation of Heme Oxygenase‐1 in Hypoxic Cardiomyocytes
Bibliographic record
Abstract
INTRODUCTION The heme metabolism pathway is a novel therapeutic target in the management of heart failure, with cytoprotection mediated through induction of heme oxygenase‐1 (HMOX1). However, translation of HMOX1‐targeted therapeutics to the clinic has not occurred. Understanding of heme bioavailability regulation in cardiomyocytes, particularly during hypoxia or heart failure, is incomplete. The molecular response to hypoxia is largely regulated by hypoxia inducible transcription factors (HIFs). HIF1α transcriptionally regulates HMOX1 in acute, severe hypoxia but the role of HIF2α in heme metabolism is unknown. A detailed understanding of the differences in molecular regulation between acute or chronic and severe or moderate hypoxia in cardiomyocytes is required. HYPOTHESIS Hypoxia‐inducible factor 2α (HIF2α) contains heme‐regulatory motifs that are sensitized by heme bioavailability at various degrees of hypoxia in cardiomyocytes to regulate the acute expression of HMOX1 in vitro and in experimental models of heart failure in vivo . METHODS Acute myocardial infarction (AMI)‐induced heart failure was modeled through permanent surgical ligation of the left anterior descending coronary artery in mice. Hypertensive heart failure was modeled through transverse aortic constriction (TAC). Expression of heme regulatory enzymes and hypoxia inducible factors were measured via Western Blot, qPCR and heme content assay. In vitro , hypoxia was established by incubating H9C2 and neonatal rat cardiomyocytes in an adjustable‐oxygen chamber. HIF1α and HIF2α were knocked down or overexpressed through adenoviral vectors. To investigate the role of heme bioavailability in HIF2α sensitization, cells were incubated with the heme surrogate, hemin. RESULTS In vivo , heme levels were increased in both AMI and TAC‐induced heart failure progressively, however not due to increased heme synthesis enzymes. In vitro , HMOX1 was increased by HIF2α more than by HIF1α overexpression. This response was synergistically increased in heme‐replete hypoxia with HIF2α, but not HIF1α, overexpression. CONCLUSIONS We have shown for the first time that HIF2α is a novel regulator of HMOX1. Further understanding of heme homeostasis in the heart is necessary to optimize therapeutic targeting of the heme metabolic pathway in heart failure. Further, we show that HIF2α has a distinct role from HIF1α as it is sensitive to heme bioavailability and not an exclusive oxygen sensor. Support or Funding Information Natural Sciences and Engineering Research Council of Canada
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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) | 0.000 | 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) | 0.002 | 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 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".