Novel Mechanisms Related to DHA’s Atheroprotective Effects in Endothelial Cells: eNOS Activity Is Regulated by DHA via p38MAPK and MSK
Bibliographic record
Abstract
Our laboratory previously reported that docosahexaenoic acid (DHA) activates p38 mitogen-activated protein kinase (MAPK) differently in growing and quiescent human endothelial cells, which represent the atherogenic and healthy states in vivo, respectively. Endothelial nitric oxide synthase (eNOS) activity differs between these two states. Since eNOS can be regulated by p38MAPK and mitogen-stimulated kinase (MSK) is a p38MAPK substrate involved in cell proliferation and inflammation, we hypothesized that DHA's atheroprotective actions require eNOS activation via the p38MAPK/MSK pathway. Thus, our objective was to investigate the role of p38MAPK/MSK in the eNOS response to DHA and determine whether the proposed pathway is growth state-sensitive. EA.hy926 cells were cultured on Matrigel-coated plates to sub-confluent and quiescent states and treated with DHA ± SB202190 or SB747651A, inhibitors of p38MAPK and MSK, respectively. eNOS activation was quantified by Western blot detection of Ser1177 phosphorylation. eNOS activation by DHA in EA.hy926 cells was concentration-, time-, and growth state-dependent. p38MAPK inhibition suppressed eNOS activity in sub-confluent cells and increased eNOS activity in quiescent cells, while MSK inhibition suppressed eNOS activity in both growth states. eNOS activity remained suppressed with DHA treatment under MSK inhibition and showed no dose- or growth state-dependent effects. In contrast, when p38MAPK was inhibited, high dose DHA activated eNOS in sub-confluent cells, but dose-dependently decreased the elevated eNOS activity of quiescent cells. eNOS activity in endothelial cells is modulated by DHA via p38MAPK and MSK. The growth state-dependent regulation of p38MAPK and eNOS by DHA provides novel insight into the molecular mechanisms of DHA's atheroprotective actions in relation to health status. Research Manitoba, St Boniface Hospital Foundation, University of Manitoba - GETS
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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 | 0.001 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.001 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 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".