Abstract 19163: Implication of DNA Damage Signaling and Epigenetic Readers in Metabolic Disorder Observed in Vascular Wall of Ischemic Patients
Bibliographic record
Abstract
Background: Coronary artery stenosis is characterized by coronary artery smooth muscle cell (CoASMC) proliferation and survival in detrimental conditions (increased inflammation, oxidized lipids, shear stress) known to cause DNA damage. In cancer, increased cell proliferation was attributed to DNA damage signaling activation secondary to mitochondrial/metabolic dysfunction. This leads to the upregulation of Poly(ADP)ribose-polymerase 1 (PARP-1), a critical enzyme acting as a DNA damage sensor, and the epigenetic reader Bromodomain-containing protein 4 (BRD4), both known to contribute to cell survival and proliferation. In light of these observations, we hypothesized that impaired mitochondria/metabolism triggers DNA damage signaling in coronary artery stenosis leading to CoASMC proliferation and thus vessel narrowing. Method/Results: Primary cultured human CoASMC from patients with stenosis (n=3) exhibit signs of mitochondrial dysfunction including hyperpolarization (TMRM; n=3, p<0.05), downregulation metabolic sensors Sirtuin 1 (SIRT1) and peroxisome proliferator-activated receptor coactivator 1 (PGC1-α) expression (western blot (WB); n=3, p<0.05). These cells also exhibit enhanced glycolysis compared to control hCoASMC (Seahorse Bioscience XF24e; n=3, p<0.05). These mitochondrial/metabolic abnormalities enhance DNA damage signaling in human coronary arteries with stenosis (53BP1; n=8, p<0.05), as well as PARP-1 and BRD4 expression (WB; n=4, p<0.05) compared to control arteries. This pathogenic phenotype is also present in isolated hCoASMC issued from stenosis, as they have more DNA damage sites (γH2AX; n=5, p<0.05) and exhibit increased PARP-1 and BRD4 expression (WB; n=4, p<0.05) compared to control hCoASMC. PARP-1 and BRD4 activation in pathologic hCoASMC promote proliferation (Ki67; n=5, p<0.05) by downregulating cell cycle inhibitors p300 and p21 (WB; n=3, p<0.05), leading to cell survival (MTT assay; n=3, p<0.05). This pathological phenotype was reversed upon treatment with a PARP-1 (Veliparib, 10μM) or a BRD4 (JQ1, 1μM) inhibitor. Conclusion: Our study suggests an important role for BRD4 signaling and metabolic disorder in coronary diseases and opens the door to new avenues of investigation and treatment.
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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) | 0.008 | 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".