Abstract 356: C/EBP α Mediates Shear Stress-Dependent Downregulation of the Angiotensin Type 1 Receptor
Bibliographic record
Abstract
The renin-angiotensin system, through the actions of angiotensin II, has significant proinflammatory actions on the vessel wall that can contribute to the progression of atherosclerosis. Hemodynamic forces are major determinants of atherosclerotic plaque localization. Plaques tend to form at arterial bifurcations, branch points, and curvatures where blood flow is low and oscillatory, whereas blood vessels exposed to high laminar shear stress remain comparatively devoid of plaques. Immunostaining of C57BL/6 mouse aortic arches showed a distinctive endothelial angiotensin type 1 receptor (AT1R) staining at the athero-prone inner curvature of the aortic arch but not in the adjoining outer curvature. In HUVECs exposed to laminar shear stress, we found that the AT1R was downregulated within 3 hours. The objective of the present study was to determine the mechanisms underlying shear stress-dependent downregulation of AT1R. We designed luciferase plasmids driven by different constructs of the AT1R promoter, spanning -1934 to +101 from the transcription start site, and transfected them into mouse primary endothelial cells. Using luciferase reporter assay, we found that shear stress reduced expression of the reporter construct by 42% (static = 3.00±0.51%, shear = 1.73±0.30%, P<0.05) after 6 hours. Using truncated constructs of the AT1R promoter, we identified the region -492 to -657 as necessary for the shear stress-dependent downregulation of AT1R (static = 1.20±0.23%, shear = 1.11±0.22%). Based on sequence conservation among human, mouse, rat and chimp, transcription factor binding site analysis pointed to a well-conserved site for C/EBP alpha. We used chromatin immunoprecipitation followed by qPCR analysis to demonstrate that C/EBP alpha was more strongly bound to the AT1R promoter under shear stress (3.21±0.83%) compared with static conditions (0.99±0.29%, P<0.05). Immunofluorescence also showed that C/EBP alpha was more abundant in the nucleus of endothelial cells under shear stress (12.7±3.0%) than static (1.9±1.6%) conditions. Our results suggest that the shear-stress dependent downregulation of AT1R is, at least in part, mediated through C/EBP alpha. This is, to our knowledge, the first indication of a role for C/EBP alpha in shear stress-dependent gene regulation.
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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 | 0.000 |
| 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) | 0.007 | 0.004 |
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".