Abstract 11283: Induction of Interferon-Stimulated Gene 15 by Pressure Overload Facilitates Adverse Ventricular Remodeling
Bibliographic record
Abstract
Introduction: Inflammation promotes adverse ventricular remodeling, a common antecedent of heart failure. Here, we set out to determine how cardiomyocytes respond to accumulating inflammatory cells within the remodeling heart and how this response, in turn, affects heart function. Methods: Experiments were performed in mouse and rat models of pressure overload, cultured mouse and human cardiomyocytes and human heart failure tissue. Results: CCR2+ monocyte-derived macrophages from Ccr2 gfp/+ mice accumulated early in mouse hearts after transverse aortic constriction (TAC) and Ccr2 knockout attenuated cardiac function decline (ejection fraction, fractional shortening, cardiac output and stroke volume). Cardiomyocyte RNA sequencing revealed that the secretome of CCR2+ cells isolated from TAC hearts induced an interferon response in cardiomyocytes, characterized by upregulation of interferon-stimulated gene 15 (ISG15), which post-translationally modifies actively translated proteins through a process termed ISGylation. ISG15 upregulation or protein ISGylation were also observed in the hearts of mice infused with angiotensin II, uninephrectomized rats treated with DOCA-salt, rats after pulmonary artery banding; mouse and human cardiomyocytes exposed to recombinant interferons; and ventricular tissue of humans with non-ischemic cardiomyopathy. ISG15 accumulated at, or close to, cardiomyocyte intercalated discs and Nano LC-MS/MS, co-immunoprecipitation and co-localization experiments identified the myofibrillar protein filamin-C to be an ISGylation target at these sites. Lastly, knockout of Isg15 attenuated cardiac function decline in mice following TAC, accompanied by a transcriptional profile indicative of preserved cardiac energetics. Conclusions: Collectively, these studies reveal that ISG15 induction is a characteristic of non-ischemic ventricular remodeling and they identify protein ISGylation as an inflammation-induced post-translational modification that may contribute to heart failure development. Strategies that prevent the ISGylation of cardiomyocyte proteins occurring during ventricular remodeling may improve heart failure outcomes.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| 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) | 0.000 | 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 teacher head, 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".