Abstract 100: Mitochondrial Dynamics Directs Macrophage Polarization During Atherosclerosis: Implications For Disease Regression
Bibliographic record
Abstract
Coronary heart disease is caused by atherosclerosis, a cholesterol-driven inflammatory disease of the vessel wall. A hallmark of atherogenesis is the accumulation of pro-inflammatory (M1) macrophages within the vessel wall, which sustains the inflammatory environment of the atherosclerotic plaque. In contrast, during disease regression, macrophages adopt a pro-resolving, anti-inflammatory phenotype (M2). Macrophage subtypes also exhibit different metabolic programs, where M1 macrophages' preferentiality use glycolytic metabolism and are associated with high levels of reactive oxygen species (ROS), while M2 macrophages primarily use oxidative metabolism. Macrophages adapt to these different metabolic needs and protect from mitochondrial DNA damage by ROS by undergoing cycles of fission (fragmentation) & fusion (elongation), which have been demonstrated to direct differentiation and function in other cell types, including T-cells. We hypothesize that the balance of mitochondrial fusion & fission directs macrophage polarization and may influence macrophage plasticity during atherosclerosis progression and regression. We found that mouse bone marrow-derived macrophages polarized to an M1 phenotype have a more elongated mitochondrial network, whereas both resting (M0) and M2 macrophages have a more fragmented mitochondrial phenotype. We find that M1 macrophages are more active with a higher number of mitochondria undergoing either a fission or fusion event compared to both M0 and M2 cells. The M1-like elongated mitochondrial phenotype can also be seen under atherogenic lipid-loading conditions. Exciting preliminary data suggests inhibiting mitochondrial fission (i.e. by knocking down three critical proteins, Drp1, Mff & Fis1) or inhibiting mitochondrial fusion (i.e. by knocking down fusion proteins Opa1, Mfn1 & Mfn2) impacts macrophages ability to polarizing into M1 or M2 phenotypes. Together these data suggest that the changes in mitochondrial dynamics direct the polarization of these macrophages and thus could be targeted to promote regression. Regression is an untapped area of atherosclerosis research, and mitochondria dynamics may be a new target to direction macrophage polarization within a lesion.
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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 | 0.001 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.004 | 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".