Abstract 19347: The Mouse Mast Cell Protease 4 is Involved in the Generation of Endothelin-1 in vitro and in vivo
Bibliographic record
Abstract
The serine protease chymase converts intravenously (iv)- administered big-endothelin-1 to endothelin-1 (ET-1) in the mouse in vivo. The mouse mast cell protease 4 (mMCP-4) is among eight chymase-like murine isoforms and is involved in the generation of angiotensin-II (Ang-II) from its precursor Ang-I. It remains to be determined which chymase isoform is involved in the endothelin-converting enzyme -independent production of ET-1. In the present study, the contribution of mMCP-4 was determined in the conversion of exogenous Big-ET-1 in vitro and in vivo as well as in the tissue production of endogenous ET-1. In vitro analyses were performed from cardiac left ventricle, aorta, kidneys and lungs homogenates derived from wild type (WT) and mMCP-4 KO mice. The pressor response in anaesthetized mice to Big-ET-1, but not ET-1 (1-31) or ET-1 was significantly reduced in mMCP-4 KO mice compared to their WT congeners. Furthermore, a selective chymase inhibitor, TY-51469, significantly reduced the pressor response to Big-ET-1 in WT but not mMCP-4 KO mice. Radio-telemetry analysis in free-moving, conscious mice revealed no differences in basal blood pressure between WT and mMCP-4 KO mice. TY-51469 also inhibited the in vitro hydrolysis a chymotrypsin-sensitive fluorogenic peptide in soluble fractions derived from WT but not mMCP-4 KO tissues. HPLC-MALDI-MS analysis revealed that supernatants from WT but not mMCP-4 KO mice could yield ET-1 (1-31) from Big-ET-1 in vitro, and that this conversion is blocked by TY-51469 in WT samples. The in vivo conversion of iv-administered Big-ET-1 to plasmatic ET-1 (1-31) and ET-1 was also reduced in mMCP-4 KO mice compared to their WT congeners. Finally, tissue levels of immunoreactive ET-1 were reduced by 40% in lung homogenates from mMCP-4 KO mice when compared to those from WT congeners. We conclude that mMCP-4 is the predominantly involved chymase isoform in the production of endogenous ET-1 in the mouse model.
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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) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.001 |
| Bibliometrics | 0.001 | 0.000 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.009 | 0.003 |
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".