Abstract 5465: SIRT1 Decreases Lox-1 Mediated Foam Cell Formation in Atherogenesis
Bibliographic record
Abstract
Background - Atherosclerosis is a chronic inflammatory disease that results from interaction between oxLDL, activated endothelial cells, monocyte-derived macrophages, T cells, and the arterial wall. Infiltrating macrophages become foam cells upon uptake of oxidized low-density lipoproteins (oxLDL) via scavenger receptors such as lectin-like oxLDL receptor-1 (Lox-1). SIRT1 is a class III deacetylase that senses caloric restriction, improves insulin secretion in islet cells, and reduces accumulation of fatty acids in white adipose. The relevance of endogenous SIRT1 on atherosclerosis remains unknown. Methods - To investigate the role of SIRT1 in these cellular and molecular processes, we compared hypercholesterolemic ApoE−/− SIRT1+/+ and ApoE−/− SIRT1+/− mice that were kept on a high-cholesterol diet for 12 weeks. Peritoneal-elicited macrophages, human aortic endothelial cells (HAEC) and RAW macrophages were used to verify our in vivo findings. Bone-marrow transplantations were performed to assess the relevance of macrophage-derived SIRT1 on atherogenesis. Results - Our plaque analyses reveal that SIRT1 prevents atherogenesis without affecting total plasma cholesterol or lipid subfractions. ApoE−/− SIRT1+/− mice show increased features of plaque vulnerability with thinner fibrous caps and enhanced plaque inflammation (increased number of macrophages and T cells as well as induced expression of adhesion molecules and inflammatory cytokines). Furthermore, peritoneal-elicited macrophages from heterozygous mice accumulate increased levels of oxLDL. In vitro, we show that the atheroprotective effects of SIRT1 are mediated via NF- κ B inhibition: in HAEC SIRT1 inhibits NF- κ B signaling and diminishes expression of adhesion molecules; in macrophages the inhibitory effect reduces expression of Lox-1. Bone-marrow transplantations demonstrate that macrophage.-derived SIRT1 is crucial for preventing disease progression. Conclusions - Our data show that SIRT1 prevents atherosclerotic plaque formation. The availability of specific SIRT1-activating drugs suggests that pharmacological activation of SIRT1 may become an attractive anti-atherogenic strategy.
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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".