The Regulation of Heme Metabolism in Myocytes by Hypoxia and Ischemia: Substrate‐Enzyme Dyssynchrony
Bibliographic record
Abstract
Current strategies for the treatment of acute myocardial infarction (AMI) are limited therefore better pharmacological interventions are needed to improve cardiac function post‐injury. Overexpression of the enzyme heme oxygenase‐1 (HMOX1) has been shown to exert cytoprotective effects in models of acute myocardial infarction and represents a highly attractive therapeutic target. HMOX1 is the stress‐inducible enzyme responsible for the catabolism of heme, the functional backbone by which oxygen is carried in proteins like hemoglobin and cytochromes in the electron transport chain. As a potent inducer of HMOX1 and an FDA‐approved heme‐surrogate for the treatment of porphyria, hemin represents a novel treatment strategy for AMI. Translation of HMOX1‐targeted therapeutics to the clinic has been stymied by a singular focus on HMOX1 and an incomplete understanding of fundamental heme metabolism regulation in response to hypoxia, ischemia or pharmacological stimulation with hemin. To date, studies investigating hemin pharmacology and its use in models of ischemic injury are limited. The objective of the present study was to provide a temporal and pharmacokinetic characterization of the changes in heme regulatory enzyme expression in response to hemin and ischemic cardiac injury (i.e. AMI). Echocardiographic, hemodynamic and protein quantification analyses were performed in male CD‐1 mice following a single intraperitoneal hemin injection, permanent ligation AMI, or daily hemin treatment pre‐ or post‐AMI with corresponding sham and vehicle controls. Temporal changes in left ventricular heme regulatory enzyme expression were measured in response to hemin and AMI. This is the first study to holistically characterize the effects of either AMI and/or hemin on endogenous heme regulation in the myocardium. Hemin markedly increased HMOX1 levels and instigated isoform switching between heme‐synthesizing enzymes in the left ventricle of healthy mice. This isoform switching was further observed with AMI and suggests a progressive increase in heme bioavailability with ischemic injury. Interestingly, HMOX1 — a heme and stress‐inducible enzyme — was induced at only 3 days post‐AMI and did not increase concomitantly with heme‐synthesizing enzymes. Echocardiographic analyses showed preserved left ventricular morphology and cardiac output with hemin administration both pre‐ and post‐AMI. Invasive hemodynamics revealed preserved left ventricular function in mice administered daily hemin when initiated 3h pre‐AMI but not when initiated 2h post‐AMI. Similarly, hemin administration significantly increased H9C2 cardiomyotubule viability when administered prior to H2O2‐mediated injury but not with simultaneous or 2h post‐injury hemin administration. This suggests that time‐dependent mechanisms are involved in conferring hemin‐mediated cardioprotection and could suggest differential mechanisms related to myocyte survival and cardiac remodelling. Support or Funding Information Natural Sciences and Engineering Research Council of Canada, Nova Scotia Health Research Foundation
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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) | 0.001 | 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".