Abstract 20130: Hypertrophic Cardiomyopathy in RAF1 Mutant-associated Noonan Syndrome Requires Complex Cellular Interplay
Bibliographic record
Abstract
Hypertrophic cardiomyopathy (HCM) has multiple etiologies, including hypertension, cardiac valve disease or genetic defects. Most inherited HCM results from defects in sarcomere proteins, but ~25% are caused by aberrant cardiac signal transduction genes. RASopathies are developmental disorders with multiple variably penetrant features, including HCM, which are caused by mutations in genes encoding RAS/extracellular signal-regulated kinase (ERK) pathway components. The most common RASopathy, Noonan Syndrome (NS), results from gain-of-function alleles in PTPN11, KRAS, SHOC2, SOS1/2, RAF1 and RIT1. Activating mutations in RAF1 are strongly (~95%) associated with HCM. Global knock-in mice harboring the NS allele Raf1L613V recapitulate the features of NS-associated HCM, including ventricular chamber dilatation, enhanced cardiac contractility, and exacerbation of pressure-overload induced fibrosis. Here, using inducible Raf1L613V knock-in mice and lineage-specific Cre lines, we show that RAF1 mutant-associated HCM is caused by a complex interplay of multiple cardiac cell types. Surprisingly, cardiomyocyte-specific Raf1L613V expression caused minimal hypertrophy, yet markedly increased cardiac contractility. By contrast, endocardial/cardiac endothelial (EC)-specific Raf1L613V expression promoted cardiomyocyte hypertrophy without affecting contractility. In direct or Transwell co-cultures, Raf1L613V-expressing ECs increased the size of normal cardiomyocytes. Cytokine arrays revealed increased IL6 secretion from isolated Raf1L613V-expressing ECs, and JAK-STAT, PI3K, and MEK/ERK activation were enhanced in EC-Raf1L613V hearts. Blocking IL6 action with neutralizing anti-IL6 antibodies reversed cardiomyocyte hypertrophy in EC/cardiomyocyte co-cultures. Finally, Raf1L613V expression in cardiomyocytes or cardiac fibroblasts, but not in ECs, exacerbated fibrosis upon pressure-overload. Taken together, our data indicate that NS HCM requires complex, cell-autonomous and -non-autonomous interactions between cardiomyocytes, ECs, and fibroblasts. Furthermore, we identify the IL6 pathway as a potential therapeutic target for RASopathy-associated HCM.
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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 | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.006 | 0.002 |
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".