2‐Methoxyestradiol protect against isoproterenol‐induced cellular hypertrophy in the human ventricular cardiomyocytes, RL‐14 cells, through MAPK‐ and NF‐κB‐dependent mechanisms
Bibliographic record
Abstract
Accumulating data supported the evidence that 2‐methoxyestradiol (2ME) is a biologically active metabolite and mediates multiple effects on the cardiovascular systems that are largely independent of estrogen receptor. 2ME is a major cytochrome P450 1B1 metabolite and has been reported to have a vasoprotective and anti‐inflammatory actions. However, whether 2ME would inhibit isoproterenol (ISO)‐induced cellular hypertrophy has not been investigated yet. Therefore, the overall objectives of the present study are to elucidate the potential anti‐hypertrophic effect of 2ME in the human ventricular cardiomyocyte, RL‐14 cells, and to explore the mechanism(s) involved. For this purpose, RL‐14 cells were treated with 100 μM ISO in the presence and absence of 200 nM 2ME. Thereafter, the cellular hypertrophy markers and cell volume were determined using real‐time polymerase chain reaction and phase contrast imaging, respectively. Phosphorylated mitogen activated protein kinases (MAPK) levels and nuclear factor kappa B (NF‐κB) binding activity were determined using a commercially available kits. Our results showed that 2ME significantly inhibited the ISO‐induced cellular hypertrophy in RL‐14 cells as evidenced by a decrease in the induction of β‐myocin heavy chain/α‐myocin heavy chain and cell volume. Mechanistically, the protective effect of 2ME against ISO‐induced cellular hypertrophy was mediated through a significant inhibition of the phosphorylated p38 and ‐Jun NH2‐terminal kinases (JNK)‐induced by ISO, whereas it normalizes the ISO‐mediated inhibition of extracellular‐regulated kinases1/2 (ERK1/2) signaling pathway. Furthermore, 2ME inhibited the ISO‐induced NF‐κB binding activity. In conclusion, our study provides the first evidence that 2ME attenuate ISO‐induced cellular hypertrophy through MAPK‐ and NF‐κB‐dependent mechanisms. Support or Funding Information This work was supported by a grant from the CIHR to A.O.S.E. Z.H.M. is the recipient Izaak Walton Killam Scholarship and Alberta Innovates‐Health solution Scholarship.
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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".