Loss of A Metalloproteinase and Disintegrin 15 leads to exacerbated myocardial hypertrophy and dilation through activation of the calcineurin pathway in male but not female micev
Bibliographic record
Abstract
Cardiac dysfunction associated with cardiomyopathies is characterized by myocardial hypertrophy and dilation involving many cellular and molecular signalling events. A disintegrin and metalloproteinases (ADAMs) are membrane-bound proteinases with diverse functions, whose role in heart disease remains underexplored. ADAM15 is expressed in the heart and is downregulated in the failing human heart. In left ventricular (LV) specimens, ADAM15 levels did not change in patients with concentric hypertrophy (preserved ejection fraction) but was markedly decreased in hypertrophic and dilated failing cardiomyopathy. We investigated the role of ADAM15 in pressure overloaded cardiomyopathy in both male and female C57BL/6 mice. Loss of ADAM15 alone did not cause cardiomyopathy in both male and female mice up to 1 year of age. Male and female wildtype (WT) and ADAM15 knockout ( Adam15 -/- ) mice were subjected to cardiac pressure overload by transverse aortic constriction (TAC) at 8 weeks of age. Adam15 -/- female mice had comparable cardiac function and hypertrophy to their WT controls while, Adam15 -/- male mice exhibited worsened decompensated hypertrophy and dilation with increased activation of mitogen activated protein kinases (pJNK, pERK1/2) compared to WT. Expression of integrin-α7 (but not integrin β1) increased significantly more in male Adam15 -/- -TAC hearts, while the interaction of integrins with basement membrane (laminin) decreased consistent with increased LV dilation. Activity of calcineurin was higher in male Adam15 -/- -TAC hearts along with greater de-phosphorylation of its target transcription factor, NFAT1. Calcineurin inhibition (cyclosporin A) blocked the excess hypertrophy and dilation in male Adam15 -/- mice post-TAC. Calcineurin signalling has been shown to be inhibited by 17β-estradiol (E2), the circulating form of estrogen. Thus, the sex-dependent phenotypic differences in male and female Adam15 -/- mice following pressure overload could be attributed to the inherent increased inhibition of calcineurin-mediated signalling due to the increased expression of estrogen in female mice. Research supported by Canadian Institutes of Health Research (CIHR) grant This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
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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".