The role of cytochrome P450 1B1 and its associated mid‐chain hydroxyeicosatetraenoic acids metabolites in the development of cellular hypertrophy induced by isoproterenol
Bibliographic record
Abstract
Heart failure is the leading cause of death, with a prevalence of over 23 million worldwide. The lifetime risk of developing heart failure is one in five. Numerous experimental studies have demonstrated the role cytochrome P450 1B1 (CYP1B1) and its associated mid‐chain hydroxyeicosatetraenoic acids (mid‐chain HETEs) metabolites in the pathogenesis of heart failure and cardiac hypertrophy. However, the ability of isoproterenol (ISO) to induce cardiac hypertrophy through mid‐chain HETEs has not been investigated yet. Therefore, we hypothesized that ISO induced cardiac hypertrophy through the induction of CYP1B1 and its associated mid‐chain HETEs metabolites. To test our hypothesis, the human ventricular cardiomyocytes, RL‐14 cells, were treated with ISO in the presence and absence of tetramethoxystilbene (TMS), a selective CYP1B1 inhibitor. Thereafter, the cellular hypertrophy markers, cell volume and mid‐chain HETEs metabolites were determined using real‐time polymerase chain reaction, phase contrast imaging and liquid chromatography‐electron spray ionization‐mass spectrometry, respectively. Our results showed that ISO induced cellular hypertrophy in RL‐14 cells as evidenced by the significant induction of β‐myocin heavy chain/α‐myocin heavy chain (β‐MHC/α‐MHC) and cell volume. Interestingly, ISO‐induced cellular hypertrophy was associated with a proportional increase in the protein expression of CYP1B1 and the formation of mid‐chain HETEs metabolites. The direct evidence for the involvement of CYP1B1 in the ISO‐induced cellular hypertrophy was supported by the ability of TMS and CYP1B1 siRNA to significantly inhibit the ISO‐mediated the induction of β‐MHC/α‐MHC and the increase cell volume. Mechanistically, the protective effect of TMS against ISO‐induced cellular hypertrophy was mediated through the inhibition of NF‐κB signaling pathway. In conclusion, our study provides the first evidence that the inhibition of CYP1B1 and hence mid‐chain HETEs attenuate ISO‐induced cellular hypertrophy. Support or Funding Information This work was supported by a grant from the CIHR to A.O.S.E.
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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 | 0.001 |
| 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".