Novel Mechanisms Related to DHA’s Atheroprotective Effects in Endothelial Cells: Modulation of Histone H3 Modification via Activation of p38MAPK Signaling
Bibliographic record
Abstract
Docosahexaenoic acid (DHA) is known for its protective effects against cardiovascular disease, which has been the leading cause of death worldwide for 2 decades. The molecular mechanisms responsible for DHA's atheroprotective effects, however, remain largely unknown. DHA has been found to activate p38 mitogen-activated protein kinase (MAPK) differently in growing and quiescent human endothelial cells, which represent dysfunctional and healthy states in vivo, respectively. This study was designed to characterize the activation pattern of p38MAPK in endothelial cells in response to DHA treatment and to identify possible downstream targets by which DHA exerts its protective effects. EA.hy926 cells were cultured on Matrigel-coated plates to sub-confluent, confluent, and quiescent states. The cells were treated with DHA to establish concentration (10 μM to 150 μM) and time course (10 min to 24 h) curves, with or without SB202190, a p38MAPK-specific inhibitor. The activation of p38MAPK and its downstream targets was quantified by Western blotting. Histone H3 modifications upon DHA treatment were tested with an ELISA-based kit. The activation of p38MAPK by DHA in EA.hy926 cells was concentration-, time-, and growth state-dependent. Upon p38MAPK inhibition, activation of mitogen and stress activated kinase 1 (MSK1), a downstream target of p38MAPK, declined. This reduction was attenuated by low concentrations of DHA in quiescent endothelial cells but not confluent or sub-confluent cells. Since MSK1 can act on histone H3 and other chromatin binding proteins like cAMP response element-binding protein (CREB), H3 modifications were monitored. In the confluent state, DHA caused a 6-fold increase in total H3, with a concomitant decrease in most methylation, acetylation, and phosphorylation marks, including H3K9me1/3, H3K27me2, H3K36me1/3, H3K9ac, H3K18ac, H3S10ph, and H3S28ph. This study showed that DHA may exert its effects in endothelial cells via the p38MAPK signalling pathway, and MSK1 may be a downstream effector possibly leading to epigenetic changes. The results provide novel insights regarding DHA's atheroprotective actions and identify new therapeutic targets with potential for treating atherosclerosis. Research Manitoba, St Boniface Hospital Foundation-Research Without Borders.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| 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 | 0.000 |
| Insufficient payload (model declined to judge) | 0.000 | 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 teacher head, 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".