Abstract 69: Angiotensin II- Canonical TGF-β Signaling Downregulates Apelinergic Pathway in Hypertension
Bibliographic record
Abstract
Background: Apelin is a novel peptide which along with its receptor, APJ, mediates apelinergic signaling. Apelinergic signaling plays a critical role in cardiovascular homeostasis, including regulation of blood pressure. While exogenous apelin blocks Angiotensin II (AngII) mediated nuclear signaling, the role and regulation of endogenous apelin in hypertension (HTN) remains obscure. We hypothesize that apelinergic pathway is downregulated in HTN, which is primarily mediated by aberrant AngII signaling. Approach: To test our hypothesis we utilized two mouse models of HTN, including AngII infusion and oral administration of N (ω)-nitro-l-arginine methyl ester (L-NAME). Blood pressure was monitored via noninvasive tail-cuff device. To determine the signaling involved we investigated the effect of AngII on apelinergic pathway in vitro. Results: Cardiac apelin was decreased significantly in both murine models of HTN. Downregulated apelin also corresponded with increased deposition of collagen, and up-regulation of senescence markers including PAI-1. Meanwhile, APJ levels were unaffected in both these hypertensive models. In our in vitro studies AngII downregulated apelin expression in human aortic endothelial cells (HAECs) and human cardiac fibroblasts (HCFs). Furthermore, our studies in AngII infused mice and in HCFs highlight the role of TGF-β-pSMAD signaling, independent of MEK involvement, in AngII induced apelin downregulation. Conclusion and Significance: Our studies demonstrate that aberrant AngII signaling downregulates apelin in HTN. This downregulation involves canonical Tgf-β1 signaling and affects apelin transcription. Importantly, we propose that AngII mediates its hypertensive pathology by decreasing apelinergic regulation. Since exogenous apelin blocks AngII signaling, further knowledge and negation of AngII induced apelin downregulation could result in the development of novel anti-hypertensive therapies.
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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 | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.003 | 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 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".