Abstract 1: Opposing Roles for Endoglin and Soluble Endoglin in Cardiac Remodeling and Heart Failure
Bibliographic record
Abstract
Transforming growth factor beta-1 (TGFb1) promotes cardiac fibrosis. The transmembrane co-receptor Endoglin (Eng; CD105) facilitates TGFb1 signaling via SMAD effector proteins. In contrast, a circulating form of soluble endoglin (sEng) inhibits TGFb1 signaling in vascular endothelium. We recently reported that increased sEng levels in human serum correlate with clinical indices of heart failure severity. Therefore, we tested the hypothesis that Eng and sEng mediate opposing effects on cardiac fibrosis in heart failure. In male, wild-type mice (WT), Eng expression increased in the left ventricle (LV) after 2, 4, and 10 weeks of thoracic aortic constriction (TAC) accompanied by progressive LV fibrosis and hypertrophy. In contrast to WT mice, Eng haploinsufficient (Eng +/− ) mice had preserved LV function (FS%: 78±4 vs 22±16, Eng +/− vs WT, p<0.01) and improved survival [88%(7/8) vs 50%(4/8), Eng +/− vs WT, p<0.001) after 10 weeks of TAC. Reduced LV fibrosis was observed in Eng +/− mice, while LV mass, cardiomyocyte hypertrophy, and calcineurin, SerCA, and bMHC expression were comparable to WT after TAC. Capillary density was significantly higher in Eng +/− mice after TAC compared to WT. LV SMAD phosphorylation (pSMAD) after TAC was studied and a preferential increase was observed in pSMAD1/5/8 expression in Eng +/− mice as compared to WT mice, in which cardiac pSmad2/3 expression was increased. The dependence of TGFb1 induced collagen synthesis on Eng expression was tested in vitro using human cardiac fibroblasts (hCF). Neutralizing antibodies and siRNA against Eng each attenuated TGFb1 induced collagen synthesis. In contrast, conditioned media from cells transfected with an adenovirus over-expressing sEng attenuated pSMAD2/3 expression and TGFb1 induced collagen synthesis in hCF. Treatment of hCF with recombinant sEng blocked TGFb1 induced collagen synthesis in a dose-dependent manner, confirming an inhibitory role of sEng. These results indicate that Eng and sEng mediate opposite effects on TGFb1 induced collagen synthesis. Reduced Eng expression uncouples cardiac fibrosis from cardiomyocyte hypertrophy, promotes SMAD1/5/8-signaling, and enhances angiogenesis. Eng may represent a novel therapeutic target to improve survival in heart failure.
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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 | 0.002 | 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".