Simultaneous subthreshold inhibition of MMP, MLCK and NOS activities protects cardiomyocytes from contractile dysfunction induced by hypoxia-reoxygenation
Bibliographic record
Abstract
I of the myocardium during ischemia/reperfusion (I/R) is a complex and multifactorial process including uncontrolled protein phosphorylation, increased production of reactive oxygen species such as nitric oxide and peroxynitrite and increased contractile protein degradation by matrix metalloproteinases (MMPs). It has been shown that inhibition of MMP-2, myosin light chain kinase (MLCK) or nitric oxide synthase (NOS) can protect the heart from contractile dysfunction triggered by I/R. In this study, we show that co-administration of a mixture of low (subthreshold) concentrations of inhibitors for MMP activity (doxycycline), MLC1 phoshorylation (ML-7 inhibitor of MLCK) and nitric oxide synthase (1400W or L-NAME) protects cardiomyocytes from hypoxia-reoxygenation (H-R) induced contractile dysfunction. Isolated cardiomyocytes were subjected to 2 min hypoxia and 20 min reoxygenation (H-R) in the presence or absence of the inhibitor cocktail. Contractility of cardiomyocytes was expressed as myocyte peak shortening. Inhibition of MMP-2 by doxycycline (25-100 μM), MLCK by ML-7 (0.5-5 μM) and NO synthase with L-NAME (25-100 μM) or 1400W (25-100 μM) protected myocyte contractility after H-R in a concentration dependent manner. This led to full recovery of contractile dysfunction induced by H-R. Mixture of NOS, MMP-2 and MLCK inhibitors in subthreshold or lower concentrations protected cardiomyocyte contractility and MLC1 from degradation by MMP-2. The results of this study suggest that administration of a mixture of low (subthreshold) concentrations of doxycycline, ML-7, and 1400W or L-NAME might to be a novel strategy for protecting cardiomyocyte contractility from oxidative stress induced by coronary revascularization during cardiopulmonary bypass.
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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".