Abstract 485: STING(ing) the Heart: How DNA Damage and Inflammation Orchestrate Cardiac Remodeling and Heart Failure
Bibliographic record
Abstract
Background: We aimed to investigate the role of DNA breaks in inducing inflammation leading to adverse remodeling, premature senescence, and cardiac dysfunction leading to onset of heart failure. Methods: in vivo : Heart-focused IR (using XRad225Cx from PXi) on adult Sprague Dawley rats; 4-5 per group; dose: 0, 15, 30, 45 Gy (endpoint 12 weeks post-IR). Serial echocardiogram and blood collection, P/V at endpoint; whole heart harvest analysis. in vitro : Primary cardiomyocytes from adult rats; human derived cardiac AC16 cell line; UVB ionizing radiation; protein extraction, western probing; gene expression analysis; immunofluorescence staining and microscopy. Results: DNA damage response, as illustrated by XRCC1 protein expression, is upregulated in multiple heart injury/failure models (TAC, MI, aging) and differ depending on cell stage and/or age ( in vitro proliferative vs differentiated AC16 cells). Using in vitro UVB radiation, exposure alters cardiomyocyte morphology, illustrated by α-actinin immunostaining, and activates innate inflammation and senescence, as illustrated by westerns and immunostaining of cGAS, STING, p16 and other relevant proteins. We demonstrate using heart-focused ionizing radiation a novel technique to induce aging related DNA damage and onset of diastolic heart dysfunction. Serial ECG show significant increase in E/A ratios at 8- and 12-week post irradiation of 30 and 45 Gy (E/A>2.0). We show P/V analysis supporting ECG data (~50% decrease in dPdt min, 2-fold increase in Tau, and significant [p<0.01] increase in End diastolic pressure, and no change in End systolic pressure). Using an inhibitor targeting cytosolic DNA sensor cGAS, we show attenuation of cardiac remodeling and expression of senescence. Conclusions: We elucidate the molecular pathway originating from the onset of DNA damage accumulation, leading to activation of specialized innate immunity proteins that ultimately upregulate inflammation and senescence. Here we uncover and connect key interactions between multiple pathways converging towards heart failure, and provide evidence for a novel therapeutic drug targeting cardiac aging.
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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 | 0.001 |
| Insufficient payload (model declined to judge) | 0.005 | 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".