The Effect of Losartan on Marfan Syndrome Is Angiotensin II Receptor Type 1 (ATR1) Independent
Bibliographic record
Abstract
Background Marfan Syndrome (MFS) leads to life threatening cardiovascular and pulmonary complications including aortic root dilation and emphysema‐like lung destruction. The new drug of choice to treat MFS is Losartan as it has been shown to reduce aortic and lung pathology in mouse models of MFS and is the focus of on‐going clinical trials. Losartan selectively blocks angiotensin receptor type I (ATR1), which is a key player in MFS pathogenesis. However, despite its promising therapeutic activity, Losartan has never been evaluated in the absences of its proposed target, and therefore genetic loss of ATR1 should protect against MFS and reveal the full potential of Losartan Hypothesis A model of MFS lacking ATR1 will prevent the cardiovascular and pulmonary phenotype of MFS and thereby confirm the mechanism of action of Losartan and reveal the full therapeutic potential of complete ATR1 blockade in MFS. Methods A MFS model lacking ATR1 was generated using a commonly used MFS model (Fibrillin C1039G) and ATR1 knockout mice (ATR1−/−). The resulting MFS ATR1−/− mice, both treated and untreated with Losartan, were used to evaluate the impact of ATR1 knockout on MFS. Aortic and lung pathology was evaluated through echocardiogram and histology while MFS skeletal manifestation were analyzed using radiography. Results Echocardiograms and histology show that both MFS and MFS ATR1−/− mice have similar aortic root dilation, aortic wall thickening and elastic fibre fragmentation in stark contrast to our hypothesis. Additionally, both MFS and MFS ATR1−/− groups demonstrate emphysema‐like airspace widening and significant changes in skeletal structure. Finally, when treated with Losartan MFS ATR1−/− mice showed similar reduction in aortic root dilation and airspace widening as MFS mice. Conclusion Data from our novel model shows that loss of the predominant ATR1 isoform fails to prevent MFS complications. Furthermore, Losartan treatment in the absence of ATR1 is still an effective therapeutic for MFS aortic and lung pathology. This suggests that the therapeutic utility of Losartan in MFS is off‐target and completely independent of ATR1. Support or Funding Information This work was supposed by funds from the Canadian Institutes of Health Research (CIHR) and fellowships to SS from CIHR and the University of British Columbia.
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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 | 0.000 |
| 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 | 0.000 |
| 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 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".