Abstract 320: Metabolic Basis Of Vascular Smooth Muscle Cell Phenotypic Switching And Atherosclerosis
Bibliographic record
Abstract
Background: Phenotypic switching of vascular smooth muscle cells (VSMC) has proven to be a key contributing factor to the development of atherosclerosis. In response to pathologic stimuli, VSMCs can undergo transdifferentiation to acquire phenotypes resembling synthetic, adipogenic, osteogenic, and macrophage-like foam cells. Increased mitochondrial fission and accompanying metabolic changes are believed to promote VSMC transdifferentiation and metabolic dysfunction in vascular diseases. Dynamin-related protein 1 (Drp1) is a GTPase that mediates mitochondrial fission; the mechanistic role of Drp1 activation in each pathologic VSMC phenotype requires further investigation. In the current study, we assessed how specific post-translational modifications (PTMs) contribute to Drp1 activation and mitochondrial metabolism in transdifferentiated VSMC phenotypes. Additionally, we explored if in vivo downregulation of Drp1 ameliorated the development of atherosclerosis in the thoracic aorta. Methods and Results: Mitochondrial dynamics and cellular metabolism were assessed in transdifferentiated VSMCs. Alterations in mitochondrial morphology were evaluated using Mitrotracker red staining and TEM. To determine the role of Drp1 in VSMC phenotypic switching, phosphorylation, O-GlcNAcylation, and acetylation of Drp1 were compared between individual VSMC phenotypes. The cellular bioenergetics of each VSMC phenotype were assessed to determine differences in the OCR and ECAR. Increased Drp1 activation correlated to alterations in the bioenergetic profile and increased metabolic dysfunction in the vasculature. Using SMC-specific Drp1 knockdown murine models, we utilized echocardiography, immunofluorescence, and histological staining to illustrate if the downregulation of Drp1 ameliorated atheroma formation and reduced VSMC phenotypic switching. Conclusions: The development of atherosclerosis is multifaceted; however, evidence has indicated that Drp1-induced mitochondrial fission differs in atherosclerotic VSMC phenotypes. By comparing the mitochondrial morphology and various PTMs of Drp1 in VSMC phenotypes, we can potentially isolate “precise” therapeutic targets to mitigate the development of 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) | 0.000 | 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 | 0.000 |
| Insufficient payload (model declined to judge) | 0.002 | 0.000 |
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".