Abstract 5812: A Novel Role of Insulin Degrading Enzyme (IDE) in Atherosclerosis: Studies Using IDE <sup>−/−</sup> Bone Marrow-Derived Cells Show Increased Lesion Development in a Bone Marrow Transplant LDL Receptor <sup>−/−</sup> Mouse Model
Bibliographic record
Abstract
Insulin degrading enzyme (IDE) hypofunction has been shown to promote Alzheimer’s disease as well as type II diabetes in humans and animal models, but it is unknown if IDE has a role in atherosclerosis. The scavenger receptor-A (SRA) plays a key role in foam cell formation as well as fatty streak development. Using affinity chromatography we previously identified a novel interaction between SRA and IDE from J774 cytosolic lysate. Utilizing a bone marrow transplant model, we tested the hypothesis that IDE knockout in bone marrow derived cells would increase atherosclerotic lesion severity in C57BL-6 mice on an LDLr −/− background fed a high fat diet. At 8 weeks of age, male and female LDLr −/− recipient mice underwent γ -irradiation to eliminate endogenous bone marrow. Recipient mice were repopulated with bone marrow from either wild type or IDE −/− , aged matched donor mice. Following 6 weeks of recovery, recipient mice were placed on a high fat diet (21% fat & 0.15% cholesterol) for 8 weeks to generate an atherosclerotic phenotype. In vivo results showed a significant increase in aortic arch lesion area in male mice (6-fold increased lesion area in IDE −/− (n=8) vs. WT (n=12), p<0.001) and a corresponding increase in aortic root lesion size (2.5-fold increased lesion area in IDE −/− (n=12) vs. WT (n=12), p<0.05). Total serum cholesterol was increased in male recipients repopulated with IDE −/− vs. WT (p<0.001). In vitro mechanistic studies using IDE −/− bone marrow-derived macrophages have revealed differences in adhesion (3.2-fold increase in non-adherent cells from IDE −/− mice vs. WT, p<0.05) as well as a difference in uptake and esterification of tritium-labeled oleate ( 3 H) into cholesterol ester (2-fold increase in acLDL incorporation of 3 H oleate in IDE −/− cells vs. WT cells). This suggests IDE plays a key role in macrophage function and foam cell formation during lesion development. To conclude, IDE −/− bone marrow-derived cells resulted in significantly greater lesion development when transplanted into LDLr −/− male mice. These results indicate a prominent role for IDE in atherosclerotic lesion formation and suggest that IDE may provide a novel target for therapeutic intervention.
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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 | 0.001 |
| 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".