P5378The methyltransferase SETD7 promotes myocardial ischemic injury by activating Hippo signalling
Bibliographic record
Abstract
Abstract Introduction Despite significant advances in coronary revascularization, acute myocardial infarction remains the leading cause of heart failure and death worldwide. The Hippo pathway is a master regulator of cell survival during myocardial ischemia. Upon cellular stress, activation of Hippo signaling leads to cytosolic retention and degradation of the pro-survival transcription factor YAP. Post-translational modifications, namely methylation, critically affect protein functionality in conditions of cellular stress. The SET domain-containing lysine methyltransferase 7 (SETD7) - which induces a specific mono-methylation of both histone and non-histone proteins - has recently emerged as key player in the pathogenesis of vascular disease. However, the role of SETD7 in the heart is largely unknown. Purpose The present study investigates whether SETD7 regulates the Hippo pathway during myocardial ischemia. Methods Neonatal rat ventricular myocytes (NRVM) were exposed to normal glucose levels or glucose deprivation (GD) for 15 h, in the presence of the selective SETD7 inhibitor [(R)-PFI-2] or its inactive enantiomer [(S)-PFI-2]. Western blot and real time PCR were employed to investigate the effects of energy stress on SETD7 and the Hippo pathway, while apoptosis was assessed by Caspase-3 activity assay. YAP localization was examined by confocal microscopy while its mono-methylation was assessed by immunoblotting. SETD7 knockout (SETD7−/−) mice and wild-type (WT) littermates (male, 8–12 weeks old) underwent 1 h of left anterior descending (LAD) coronary artery ligation followed by 24 h of reperfusion. Infarct size was assessed by TTC staining and shown as infarct size per ventricle surface (I/V). Cardiac function was investigated at 24h by conventional and Tissue Doppler Imaging echocardiography (Vevo 3100, Visualsonics). Results GD for 15h in NRVMs led to both YAP phosphorylation and mono-methylation, and subsequent cytosolic retention, as assessed by confocal microscopy. Reduced nuclear content of YAP was confirmed by downregulation of YAP-dependent pro-survival genes, namely Ctgf and Fgf2. GD-induced YAP inactivation was associated with an increase in SETD7 expression. Interestingly, pharmacological inhibition of SETD7 by (R)-PFI-2 blunted YAP mono-methylation, thus restoring nuclear retention of YAP and transcription of pro-survival genes in GD-treated NRVMs. Moreover, (R)-PFI-2 prevented NRVMs apoptosis. In line with our in vitro findings, SETD7−/− mice showed decreased infarct size as compared to WT littermates (I/V: 16.27%±2 vs. 20.54%±3, p<0.005, respectively). Consistently, cardiac function, as assessed by ejection fraction (EF: 46%±2 vs. 38%±5, p<0.001), fractional shortening (FS: 22%±1 vs. 18%±3, p<0.001) as well as by TDI, was preserved in mice lacking SETD7 as compared to WT animals. Conclusions Pharmacological modulation of SETD7 by (R)-PFI-2 may represent a novel therapeutic approach to prevent myocardial ischemic damage.
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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".