Left ventricular response in the transition from hypertrophy to failure recapitulates distinct roles of Akt, β-arrestin-2, and CaMKII in mice with aortic regurgitation
Bibliographic record
Abstract
Background: Although aortic regurgitation (AR) is a clinically important condition that is becoming increasingly common, few relevant murine models and mechanistic studies exist for this condition. In this study, we attempted to delineate the pathological and molecular changes and address the roles of some potentially relevant molecules in an animal model of surgically induced AR. Methods: AR was induced by puncturing the aortic valve leaflets in C57BL/6J mice under echocardiographic guidance. Results: As early as 1 week following AR, the left ventricles (LV) displayed marked impairments in diastolic function and coronary flow reserve (CFR), as well as cardiac hypertrophy and chamber dilatation at both end-systole and end-diastole. LV free wall thickening and cardiomyocyte hypertrophy in LV were observed 2 weeks following of AR while a decline in ejection fraction was not seen until after 4 weeks. Nppa (natriuretic peptide A) and Nppb (natriuretic peptide B) increased over time, in conjunction with prominent Akt activation as well as slight CaMKII (Ca2+/calmodulin-dependent protein kinase II) activation and biphasic changes in β-arrestin-2 expression. Treatment of AR mice with Akt inhibition exacerbated the eccentric hypertrophy, while neither inhibition of CaMKII nor β-arrestin-2 overexpression influenced the response to AR. Conclusions: Our structural, functional, molecular and therapeutic analyses reveal that Akt, but not CaMKII or β-arrestin-2, plays a regulatory role in the development of LV remodeling after AR in Mice. These results may shed important light on therapeutic targets for volume overloaded cardiomyopathy.
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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 | 0.000 | 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 | 0.000 |
| 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".