Abstract 615: Absence of RIP3 Reduces Atherosclerotic Progression in Type 1 Diabetes
Bibliographic record
Abstract
Introduction: Patients suffering from Type 1 diabetes (T1D) have increased risk of developing atherosclerosis. T1D is a chronic autoimmune metabolic disease characterized by a deficiency in insulin secretion and hyperglycemia, promoting oxidative stress and low-grade inflammation in part via advanced glycation end products (AGE). Recently, we and others showed that necroptosis, a newly defined pro-inflammatory programmed cell death, drives advanced atherosclerosis. Given that diabetes accelerates inflammation and atherosclerosis, we hypothesized that hyperglycemia may exacerbate macrophage necroptosis to drive atherosclerotic lesion formation. Methods/Results: Male Ldlr-/- mice were lethally irradiated, transplanted with bone-marrow from WT or Rip3 -/- mice and then administered streptozotocin (STZ) or vehicle daily for 5 days to induce T1D, prior to being fed a western diet for 6 wks. As expected, STZ-treated WT BMT Ldlr -/- mice had a marked increased in atherosclerotic aortic lesion area compared to non-diabetic mice (1.08%±0.30 vs 2.13%±0.45). which was blunted in Rip3 -/- BMT Ldr -/- mice (arch: 49% reduction, sinus: 54% reduction, p<0.05). Bone marrow derived macrophages (BMDMs) cultured in high glucose (HG) increased cell death in response to necroptotic stimuli (oxidized LDL ± caspase inhibitor zVAD) relative to those cultured in low glucose (LG). Further, the addition of recombinant s100A8/9, a soluble AGE, markedly amplified oxLDL-induced death in HG cultured BMDMs with minimal effects on LG cultured BMDMs, suggesting that pro-inflammatory AGEs released in diabetes can augment macrophage cell death. Further, the increased cell death induced by oxLDL+S100A8/9 was inhibited by a necroptotic inhibitor, Nec-1, or in Rip3 -/- BMDMs cultured in HG. Mechanistically, treatment of BMDMs cultured in HG with oxLDL+s100A8/9 increased the expression of Rip3 and Mlkl (~5-fold and ~2-fold respectively), which may drive necroptotic cell death during hyperglycemia. Conclusion: Deletion of Rip3 markedly halts atherosclerotic progression in a STZ-induced T1D mouse model by inhibiting macrophage necroptosis induced by both atherogenic ligands (oxLDL) and soluble AGE products (s100A8/9).
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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) | 0.001 | 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 | 0.000 | 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".