A2921 In vivo miR-431–5p knockdown protects against angiotensin II-induced hypertension and vascular injury
Bibliographic record
Abstract
Objectives: Vascular injury is an early manifestation and a cause of end-organ damage in hypertension. We profiled vascular injury-associated microRNAs (miRs) to identify key miR regulators of gene expression that could be used as novel therapeutic targets. Methods: Ten week-old male C57BL/6 mice were infused SC or not with angiotensin (Ang) II for 14 days. Blood pressure (BP) was measured by telemetry. RNA was extracted from mesenteric arteries (MA) and used for small RNA and total RNA sequencing using Illumina HiSeq-2500. A candidate gene approach was used to identify potential key miR regulators involved in Ang II-induced vascular injury. Their regulatory mechanism was validated using human vascular smooth cells (VSMCs). We then tested whether intravenous injection of miR inhibitors protects against Ang II-induced BP elevation, MA injury by pressurized myography, and oxidative stress by dihydroethidium staining. Results: Ang II infusion caused MA differential expression of 35 miRs that are part of an important miR-transcription factor (TF) co-regulatory network modulating genes involved in extracellular matrix and developmental processes. The up-regulated miR-431-5p was identified as a potential key regulator. Gain- and loss-of-function in VSMCs demonstrated that miR-431-5p directly targets the TF Ets homologous factor (EHF), leading to up-regulation of collagen type I alpha 1 chain, miR-431-5p and miR-382-5p through EHF down-regulation. IV injections of miR-431-5p inhibitors delayed Ang II-induced BP elevation, and reduced MA dysfunction, stiffening and oxidative stress in mice. Conclusion: This study identified miR-431-5p as a key regulator in Ang II-induced vascular injury. miR-431-5p knockdown possesses potential value for the treatment of hypertension and vascular damage.
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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 | 0.001 | 0.001 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 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) | 0.000 | 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".