Abstract 19780: ABCA1 Response to Atherogenic Lipid Exposure is Reduced in Cultured Human Aortic Smooth Muscle Cells Compared to Human Monocyte-Derived Macrophages
Bibliographic record
Abstract
Introduction: Retention of low density (LDL) and other apolipoprotein B (apoB)-containing lipoproteins in the intima of the artery wall initiates atherosclerotic lesion formation. It has been commonly thought that the majority of the lipid overloaded “foam cells” in atherosclerosis are of leukocyte origin. Recently we reported that ≥ 50% of the foam cells in coronary artery atherosclerosis are of smooth muscle cell (SMC) origin, and that the rate-limiting cholesterol exporter, ATP-binding cassette transporter protein A1 (ABCA1), has reduced expression in intimal SMCs compared to leukocytes. Upregulation of ABCA1 expression is dependent on normal flux of lipoprotein-derived cholesterol out of lysosomes. Mechanisms by which macrophages process and store lipoprotein-derived cholesterol in lysosomal and cytosolic compartments are well described, whereas less is known about SMCs. Hypothesis: Human aortic SMCs have reduced ABCA1 levels compared to macrophages in response to atherogenic lipoprotein exposure. Methods: Conditions were optimized to load human aortic SMCs and macrophages with aggregated LDL for 24 hrs, followed by a 24 hr equilibration without lipids to allow lysosomal processing of lipoproteins. Cellular cholesterol and cholesteryl ester mass were measured using HPLC tandem mass spectrometry. Response levels to lipid loading were investigated by Western blot for ABCA1. Results: Cholesteryl ester mass in macrophages increased from 1.5±1.8 to 345.4±21.6 nmol/mg protein in response to aggregated LDL, and 17.4±8.7 to 74.0±16.0 nmol/mg protein in SMCs (mean±SEM, n=9-12 replicates). In macrophages fold change in ABCA1 with exposure to aggLDL was 2.24±0.31 (mean±SEM, n=8 replicates). Preliminary data indicate no significant increase in ABCA1 in SMCs with aggLDL loading. Confocal microscopy indicates increased lipid accumulation following aggLDL loading in the lysosomes of SMCs but not macrophages. Conclusions: These data suggest that impaired lysosomal processing of excess atherogenic lipoproteins is responsible for impaired upregulation of ABCA1 in cultured human aortic SMCs when compared to macrophages. This provides a potential mechanism for preferential formation of smooth muscle foam cells in human atherosclerosis.
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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) | 0.000 | 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) | 0.006 | 0.002 |
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".