Targeting macrophage necroptosis for therapeutic and diagnostic interventions to treat atherosclerosis
Bibliographic record
Abstract
Atherosclerosis is a disease of maladaptive inflammation driven primarily by macrophages, and as the atherosclerotic plaque progresses and becomes more complex, a necrotic core forms that ultimately underlies the instability that drives plaque rupture and myocardial infarction. Necroptosis or ‘programmed necrosis’ is an emerging cell death pathway involving kinases RIP3 and MLKL that in contrast to apoptosis, induces a pro‐inflammatory state. We hypothesize that macrophages undergo necroptosis in response to atherogenic stimuli in the vessel wall, and this process underlies necrotic core formation and plaque instability. Here, we show that oxidized LDL (oxLDL) induces necroptotic cell death in macrophages, which can be blocked by Nec‐1, a necroptosis inhibitor. Macrophages treated with oxidized LDL have increased expression of necroptotic genes RIP3 and MLKL through activation of the promoter region and increased RIP3 and MLKL phosphorylation‐ critical steps in the execution of necroptosis. Further, the combined treatment with oxLDL and DAMPs (damage associated molecular patterns) amplified macrophage necroptotic cell death, indicating that additional inflammatory stimuli present in the lesion could act synergistically to promote necroptosis. In a model of established atherosclerosis, Nec‐1 intervention in Apoe −/− mice reduced lesion size (p<0.05) and markers of plaque instability, including reduced necrotic core formation (62.6% reduction, p<0.01). Further, we developed a novel 123 I‐Nec‐1 radiotracer targeting the necroptosis pathway and show that it specifically localizes to and tightly correlates with atherosclerotic lesions. Lastly, in humans with unstable carotid atherosclerosis, expression of the necroptotic genes RIP3 and MLKL is elevated and MLKL phosphorylation is detected in advanced atheromas, indicating that the necroptotic pathway is highly activated in vulnerable plaques. In conclusion , our findings offer molecular insight into the mechanisms by which inflammatory atherogenic ligands drives cell death necrotic core formation that underlies unstable atherosclerosis and identify innovative diagnostic and therapeutic tools to treat 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) | 0.001 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.001 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 0.002 |
| Insufficient payload (model declined to judge) | 0.002 | 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".