Abstract 655: 4-Phenylbutyrate in Drinking Water Reduced Atherosclerotic Lesion Growth in ApoE-/- Mice by Modifying Monocyte-Macrophage Differentiation
Bibliographic record
Abstract
Cardiovascular disease and atherothrombosis account for the majority of deaths worldwide. Plaque rupture, thrombus formation, and vessel occlusion contribute to the acute clinical manifestations of atherothrombosis. Previously we have shown that the unfolded protein response (UPR) has an important role in monocyte-macrophage differentiation. Furthermore, macrophage infiltration, lipid accumulation and foam cell formation are key events in atherogenesis. Endoplasmic reticulum (ER) stress-dependent apoptosis also contributes to atherosclerotic lesion growth and plaque necrosis. The aim of the current study was to examine whether 4-phenylbutyrate (4-PBA), a small chemical chaperone that alleviates ER stress, confers protection against atherosclerosis when provided via drinking water. To investigate the ability of 4-PBA to affect atherosclerotic lesion growth, at 12 weeks of age female ApoE-/- mice on chow diet were provided with 4-PBA (1 - 2.5 g/kg/d) in their drinking water for five weeks, ad libitum. Following treatment, mice were sacrificed, their tissues collected and atherosclerotic lesions examined by immunohistochemistry. Early atherosclerotic lesion area was significantly reduced in ApoE-/- mice provided 4-PBA-treated water from 12 - 17 weeks of age, relative to controls (0.6 x105 ± 0.1 μm2 versus 1.1 x105 ± 0.1 μm2, respectively, P < 0.05). We hypothesized that 4-PBA drinking water decreased lesion size by a mechanism involving reduced ER stress and monocyte-macrophage differentiation. In support of this mechanism, preliminary data indicates 4-PBA inhibited monocyte-macrophage differentiation, as measured by mRNA expression of the macrophage marker MSR-1 (0.5 ± 0.2 fold-change vs. control) and cell adherence (37 ± 5% vs. control) in PMA-treated THP-1 cells. In summary, these findings provide evidence that 4-PBA-treated drinking water reduced atherosclerotic lesion size in a mouse model of atherosclerosis. We hypothesize that 4-PBA acts in part through its ability to reduce ER stress and modulate monocyte/macrophage differentiation and function. Additional studies are in progress to further examine the mechanisms by which 4-PBA affects atherogenesis.
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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) | 0.001 | 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 | 0.001 | 0.002 |
| 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".