Inhibition of matrix metalloproteinases prevents peroxynitrite‐induced contractile dysfunction in the isolated cardiac myocyte
Bibliographic record
Abstract
BACKGROUND AND PURPOSE: The potent oxidant peroxynitrite (ONOO(-)) induces mechanical dysfunction in the intact heart in part through activation of matrix metalloproteinase-2 (MMP-2). This effect may be independent of the proteolytic actions of MMPs on extracellular matrix proteins. The purpose of this study was to examine the effects of ONOO(-) on contractile function at the level of the single cardiac myocyte and whether this includes the action of MMPs. EXPERIMENTAL APPROACH: Freshly isolated ventricular myocytes from adult rats were superfused with Krebs-Henseleit buffer at 21 degrees C and paced at 0.5 Hz. Contractility was measured using a video edge-detector. ONOO(-) or decomposed ONOO(-) (vehicle control) were co-infused over 40 min to evaluate the contraction cease time (CCT). The effects of ONOO(-) on intracellular [Ca(2+)] were determined in myocytes loaded with calcium green-1 AM. MMP-2 activity was measured by gelatin zymography. KEY RESULTS: ONOO(-) (30-600 microM) caused a concentration-dependent reduction in CCT. Myocytes subjected to 300 microM ONOO(-) had a shorter CCT than decomposed ONOO(-) (14.9+1.5 vs 32.2+3.5 min, n=7-8; P<0.05) and showed increased MMP-2 activity. The MMP inhibitors doxycycline (100 microM) or PD 166793 (2 microM) reduced the decline in CCT induced by 300 microM ONOO(-). ONOO(-) caused shorter calcium transient cease time and significant alterations in intracellular [Ca(2+)] homoeostasis which were partially prevented by doxycycline. CONCLUSIONS AND IMPLICATIONS: This is the first demonstration that inhibition of MMPs protects the cardiac myocyte from ONOO(-)-induced contractile failure via an action unrelated to proteolysis of extracellular matrix proteins.
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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) | 0.001 | 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".