Abstract 825: Attenuation of Cardiac Fibrosis by Scleraxis Gene Deletion Improves Pressure Overload-Induced Cardiac Remodeling
Bibliographic record
Abstract
Cardiac fibrosis is a significant independent risk factor for heart failure with increasing incidence. The fibrotic myocardium shows increased arrhythmogenesis, and poor pumping and relaxation due to greater tissue stiffness. A critical step in this process is the conversion of fibroblasts to myofibroblasts, which are responsible for excessive extracellular matrix (ECM) production; limiting this conversion may reduce fibrosis and restore cardiac function. We previously reported that the transcription factor scleraxis, following mechanical stretch or TGFβ signaling, is both sufficient and necessary to convert fibroblasts to myofibroblasts by direct transcriptional control of myofibroblast genes including collagens, α-smooth muscle actin and fibronectin. In a pressure overload transverse aorta constriction (TAC) mouse model analyzed by echocardiography, we found that fibroblast-specific scleraxis gene deletion prior to TAC using a tamoxifen-inducible TCF21-Cre/loxP approach attenuated both systolic (LV ejection fraction, fractional shortening) and diastolic (early and late filling velocity) dysfunction, as well as chamber dilation, despite persistent hypertrophy. Functional improvement was matched by an almost complete attenuation of cardiac fibrosis (Masson’s trichrome; qPCR and western blots for fibrillar collagens and ED-A fibronectin). Scleraxis deletion also prevented induction of the myofibroblast marker periostin, suggesting a failure of scleraxis-null fibroblasts to convert to myofibroblasts. We next tested if scleraxis deletion 4 weeks post-TAC could reverse subsequent remodeling at 8 weeks post-TAC. Adverse remodeling occurred in all animals 4 weeks post-TAC (prior to scleraxis deletion), but cardiac function and chamber dimensions subsequently declined further in scleraxis-intact animals, while scleraxis-deleted animals showed preserved or improved cardiac function and morphology. Our results demonstrate that scleraxis is required for the initiation and progression of cardiac fibrosis, and that reducing fibrosis alone improves cardiac performance and morphology even in the presence of persistent pressure overload. Scleraxis is thus an important target for anti-fibrotic therapy development.
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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 | 0.001 | 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".