C-type Natriuretic Peptide Modulates TGF-β1-induced Synthesis of Proteoglycan by VICs
Why this work is in the frame
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Bibliographic record
Abstract
Abstract Aortic valve disease (AVD) is a cell-mediated pathology marked by unchecked remodeling of the extracellular matrix (ECM). This process is thought to be promoted by increased levels of TGF-β1 in the valve leaflets and the concomitant loss of protective factors such as C-type natriuretic peptide (CNP). Among its many functions, TGF-β1 stimulates the expression of proteoglycan (PG), in part via mitogen activated protein kinase (MAPK)-mediated Smad signalling. We and others have observed the formation of PG-rich lesions in early diseased aortic valves. Here we investigated the relationship between TGF-β1, CNP, and PG in a mouse model of early AVD and in vitro. Male wild-type (WT) C57Bl/6J mice were fed a control diet or BioServ F3282, a high-fat, high-carbohydrate diet (HF/HC) with 58.7% kcal from fat (cholesterol < w/w) for four months (n = 4-6 per group). Longitudinal aortic valve sections from formalin-fixed and paraffin-embedded hearts were stained by Movat’s pentachrome and immunostained for CNP and TGF-β1. Valve interstitial cells (VICs) were isolated from healthy porcine aortic valves and treated in vitro with 5 ng/ml TGF-β1 and/or 1 µM CNP or 10 µM U0126 (inhibitor of MEK, upstream of the MAPK Erk1/2) for up to 6 days. Erk1/2 phosphorylation was measured by Western blot, while PG expression in media collected from these cultures was assayed by Alcian Blue guanidine-HCL solubilisation. Mice on the HF/HC diet for four months became obese, developed mild hypercholesterolemia, and had early AVD, as demonstrated by hemodynamic dysfunction and significant thickening of the leaflets (data shown in another abstract). Thickening was due to PG deposition (11435 ± 7681 vs. 5448 ± 2948 µm2, p < 0.01), not increased collagen content (1729 ± 815 vs. 1771 ± 663 µm2, p = 0.87). TGF-β1 levels were elevated in leaflets of mice on the HF/HC diet, particularly in the region of PG lesions. The PG lesions in HF/HC mice also had lower CNP expression than non-lesion regions. In VICs, TGF-β1 induced a 29% increase of PG expression (p < 0.05), which was significantly reduced by the addition of CNP (p < 0.05). Interactions between TGF-β1 and CNP in PG synthesis were mediated in part via Erk1/2 signaling, as TGF-β1 increased Erk1/2 phosphorylation, CNP abrogated TGF-β1-induced Erk1/2 activation, and blocking Erk1/2 signaling with U0126 significantly reduced PG expression (p = 0.06). These studies demonstrate that in early AVD, thickened leaflets are PG-rich with elevated expression of TGF-β1 and down-regulated CNP. Furthermore, TGF-β1 induces PG expression in VICs, a process which is inhibited by CNP – possibly through Erk1/2. Insight into the mechanisms by which TGF-β1 and CNP regulate the formation of PG lesions helps further our understanding of early disease progression and may aid in identifying novel medical strategies to arrest this disease before a substantive and possibly untreatable burden of calcification occurs.
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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 | 0.001 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.001 |
| 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 it