Abstract 50: High-Density Lipoprotein Protects Macrophages Against Apoptosis in a PDZK1-Dependent Manner
Bibliographic record
Abstract
Macrophage apoptosis contributes to the formation of necrotic cores in atherosclerotic plaques, increasing the risk of plaque rupture, leading to clinical heart attack. Previous work from our group showed that HDL is able to protect macrophages against apoptosis, and that such protection requires HDL’s receptor protein scavenger receptor class B, type I (SR-BI). In this study, we hypothesize that this protection requires not only SR-BI, but also SR-BI’s adaptor protein PDZK1. We incubated mouse peritoneal macrophages with or without lipoproteins and triggered apoptosis with thapsigargin or tunicamycin. Cell apoptosis was assessed by annexinV, terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) and cleaved caspase-3 staining. Only low levels (~5% of cells) of apoptosis were observed in macrophages treated with thapsigargin or tunicamycin when they were cultured with lipoproteins. However thapsigargin or tunicamycin stimulated apoptosis increased ~4 fold when lipoproteins were removed from the culture medium. The addition of 50μg/ml of purified HDL (P<0.05), but not LDL, to lipoprotein-deficient medium suppressed apoptosis. However, HDL did not inhibit cell apoptosis when PDZK1 was deleted. Our time-course study showed that incubation with HDL increased phosphorylation of Akt1, Foxo3a and Erk1/2 and reduced Bim in wild type (WT), but not PDZK1-/- macrophages. In order to test the role of PDZK1 in vivo, LDLR-/- mice were transplanted with either PDZK1-/- (n=12) or WT (n=12) bone marrow and challenged with high fat diet to induce atherosclerosis. The cross-sections of aortic sinus were stained with H&E to visualize plaques. The relative necrotic core area was significantly larger (P<0.05) in PDZK1-/- group (98187.2±8076.1) than that in WT control (27279.6±16688.7). Also, compared to LDLR-/- mice transplanted with WT bone marrow, the ones with PDZK1-/- bone marrow have 2.2-fold increased TUNEL(+) (P<0.05) and 3.6-fold increased cleaved caspase-3(+) (P<0.01) macrophages in plaques. In conclusion, PDZK1 is required for the HDL-dependent protection against macrophage apoptosis. In atherosclerotic plaques, PDZK1 plays a role in protecting macrophages from apoptosis and suppressing the development of necrotic cores.
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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 | 0.001 |
| Insufficient payload (model declined to judge) | 0.006 | 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".