CARDIAC-SPECIFIC KNOCKOUT OF CAPN4 ATTENUATES MYOCARDIAL REMODELLING AND IMPROVES FUNCTION AFTER MYOCARDIAL INFARCTION IN MICE
Bibliographic record
Abstract
Objectives Calpain has been implicated in myocardial injury after myocardial infarction (MI). However, no direct evidence is available on the role of calpain in post-MI myocardial remodelling and dysfunction. The present study investigated the effects of cardiomyocyte-specific knockout of Capn4, essential for calpain-1 and calpain-2 activities on myocardial remodelling and function following MI. Methods A novel mouse model with cardiomyocyte-specific deletion of Capn4 (Capn4-ko) was generated; MI was induced by left coronary artery ligation; Left ventricular pressure–volume loop and Echocardiography were used to assess changes in left ventricle geometry and function; Sirius red staining was used for analysis of myocardial collagen deposition; Paraffin sections were stained for membranes with FITC-conjugated wheat germ agglutinin (WGA) and for nuclei with DAPI For cardiomyocyte cross-sectional area; Apoptosis was assessed by caspase-3 activity measurement and TUNEL staining; MMP-2 and MMP-9 activities in heart tissue lysates were assessed by using MMP-2 and MMP-9 Assay Kits, respectively. Results Deficiency of Capn4 significantly reduced the protein levels and activities of calpain-1 and calpain-2 in the Capn4-ko heart. In vivo cardiac function was significantly improved in Capn4-ko mice at 7 and 30 days after MI compared with their wild-type littermates. Deletion of Capn4 reduced adverse remodelling after MI as evidenced by limitation of infarct expansion and infarct zone thinning, and prevention of left ventricle dilation of Capn4-ko mice. Furthermore, myocardial collagen deposition and cardiomyocyte cross-sectional areas were significantly attenuated in Capn4-ko mice, which were accompanied by down-regulation of pro-fibrotic genes and hypertrophic genes. These effects of Capn4 knockout correlated with a decrease in cardiac apoptosis in the peri-infarct area, down-regulation of inflammatory mediators and normalisation of matrix metalloproteinase (MMP)-9 activity in the non-infarct areas of Capn4-ko mice after MI. Conclusions Cardiomyocyte-specific knockout of calpain attenuates myocardial adverse remodelling and improves myocardial function after MI. These beneficial effects of calpain disruption may result from inhibition of cardiac apoptosis, inflammation and MMP-9 activity.
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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".