GW24-e2975 Over-expression of calpastatin aggravates <i>in vitro</i> and <i>in vivo</i> cardiotoxicity induced by doxorubicin
Bibliographic record
Abstract
Objectives Doxorubicin often causes damage to the heart, which may present as cardiomyopathy. However, the mechanisms by which doxorubicin induces cardiotoxicity remain not fully understood and effective prevention for doxorubicin cardiomyopathy is not available. Calpains, which are a family of calcium-dependent thiol-proteases, have been implicated in cardiovascular diseases. Their activities are tightly inhibited by calpastatin. This study used transgenic mice overexpressing calpastatin to study the role of calpain in doxorubicin-induced cardiotoxicity. Methods The models of doxorubicin-induced cardiotoxicity were created by challenging the mice with 20 mg/kg doxorubicin intraperitoneally. Cardiomyocytes apoptosis was assayed by caspase-3 activity assay, DNA fragmentation ELISA and Annexin-V staining. Calpain activities in tissue and cultured cardiomyocytes in situ extracts were detected by using a fluorescence substrate Nsuccinyl-LLVY-AMC. ROS production was measured using DCF-DA molecule probe. Neonatal cardiomyocytes were infected with adenoviral vectors containing human calpain-1, calpain-2, calpastatin or beta-gal as a control at a multiplicity of infection of 100 PFU/cell. Cardiac function was determined by echocardiography and hemodynamic measurements. Results Doxorubicin decreased calpain activities in cultured neonatal mouse cardiomyocytes and in vivomouse hearts, which correlated with down-regulation of calpain-1 and calpain-2 proteins. Over-expression of calpastatin or treatment with pharmacological calpain inhibitors aggravated apoptosis in neonatal and adult cardiomyocytes caused by doxorubicin. On the while, over-expression of calpain-2 but not calpain-1 decreased doxorubicin-induced apoptosis in cardiomyocytes. The pro-apoptotic effects of calpain inhibition were concerned with down-regulation of AKT protein and mRNA expression, and a concomitant reduction in GSK-3 beta phosphorylation (Ser9) in doxorubicin-treated cardiomyocytes. Inhibiting AKT further increased doxorubicin-induced cardiac injuries, suggesting the effects of calpain inhibition may be mediated through inactivating the AKT signalling. In an in vivomodel of doxorubicin-induced cardiotoxicity, overexpression of calpastatin aggravated myocardial dysfunction in transgenic mice 5 days after doxorubicin treatment. The fiveday mortality was much higher in transgenic mice (29.16%) compared with their wild-type littermates (8%) after doxorubicin treatment. Conclusions Over-expression of calpastatin aggravates doxorubicin-induced cardiac injuries by calpain inhibition and thus, calpains may protect cardiomyocytes against doxorubicin-induced cardiotoxicity.
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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".