P38 MAP kinase in valve interstitial cells is activated by angiotensin II or nitric oxide/peroxynitrite, but reduced by Toll-like receptor-2 stimulation.
Bibliographic record
Abstract
BACKGROUND AND AIM OF THE STUDY: The involvement of p38 MAPK in mediating factors that may produce aortic valve disease is unknown. Angiotensin II (Ang II) has been implicated in the development of aortic stenosis through either the generation of free radicals and/or the modulation of inflammatory responses. A variety of proinflammatory factors utilize Toll-like receptors, and these may also play a role in the development of aortic valve disease. METHODS: Valve interstitial cells (VICs) were cultured from porcine aortic valves. Cells were treated with Ang II, 3-morpholinosydnonimine (SIN-1), which liberates NO and superoxide anion generating peroxynitrite, or the lipopetide Toll-like receptor-2 (TLR-2) agonist Pam3CSK4. RESULTS: In response to Ang II (1 microM), MAPK phosphorylation levels were increased by 3.5-fold after 15 min, peaked at 4.6-fold after 60 min, and decreased to 1.9-fold greater than control after 120 min of treatment. In response to SIN-1, phosphorylation levels were increased progressively throughout the 90 min of treatment and were significantly (p < 0.05) twofold (1.9 +/- 0.3) greater than control or native p38 MAPK (2.3 +/- 0.4) after 90 min. SB202190, a relatively selective inhibitor of the p38a MAPK isoform, reduced SIN-1-induced p38 MAPK phosphorylation. In contrast, there was a rapid and marked decline in phosphorylated p38 MAPK, in response to Pam3CSK4 that was evident at 30 min; after 90 min, the p38 MAPK level was 85% lower than baseline. CONCLUSION: p38 MAPK is present in VICs, and is activated by Ang II. Peroxynitrite similarly increased p38 MAPK phosphorylation, which suggests that these two factors involve similar pathways in their effect on VICs. Alternatively, peroxynitrite may be involved in the pathway by which Ang II activates p38 MAPK. The dramatic reduction in p38 MAPK phosphorylation by TLR-2 stimulation excludes a role for this receptor type in mediating Ang II or peroxynitrite effects, and suggests that inflammatory factors that act through TLR-2 to dephosphorylate p38 MAPK utilize pathways different from Ang II or peroxynitrite, to produce their effect on the aortic valve.
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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 | 0.000 |
| Insufficient payload (model declined to judge) | 0.003 | 0.001 |
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".