Methylation of the hippo signalling effector YAP by SETD7 drives myocardial ischemic injury
Bibliographic record
Abstract
Abstract Introduction Myocardial ischemia/reperfusion (I/R) injury is one of the most deleterious cardiovascular conditions and a leading cause of mortality. The Hippo pathway effector YAP critically regulates cardiomyocyte proliferation and survival during myocardial I/R injury. However, the mechanisms regulating YAP activation in this setting remain poorly understood. Post-translational modifications of proteins, namely methylation, modulate pathways implicated in myocardial I/R injury. The methyltransferase SETD7 is emerging as a regulator of cell survival via methylation of histone and non-histone proteins. Whether SETD7 participates to myocardial I/R injury remains elusive. Purpose To investigate the role of SETD7 in regulating Hippo signaling during myocardial I/R injury. 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 activity was assessed through chromatin immunoprecipitation assay (ChIP), its localization was examined by confocal microscopy while 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 (TDI) echocardiography. Results GD in NRVMs led to upregulation of SETD7 and physical interaction with the pro-survival transcriptional cofactor YAP, resulting in its direct mono-methylation. Furthermore SETD7-dependent methylation of YAP led to its cytosolic retention and subsequent reduction of YAP binding to the promoter of pro-survival genes. Of note, pharmacological inhibition of SETD7 by (R)-PFI-2 blunted YAP mono-methylation while restoring its nuclear retention. Mechanistically, SETD7 inhibition promoted YAP binding to catalase and superoxide dismutase (SOD) gene promoters, thus preventing GD-induced mitochondrial oxidative stress and apoptosis. In line with our in vitro findings, SETD7−/− mice showed decreased infarct size as compared to WT littermates and preserved cardiac systolic (ejection fraction, fractional shortening) and diastolic function, as assessed by both conventional and TDI echocardiography. Conclusions We show that SETD7-dependent methylation of YAP is required for its inactivation, thus leading to myocyte oxidative stress and apoptosis. Pharmacological modulation of SETD7 by (R)-PFI-2 may represent a new therapeutic approach to prevent myocardial ischemic damage through modulation of the Hippo pathway. Funding Acknowledgement Type of funding source: Foundation. Main funding source(s): Swiss Heart Foundation
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| 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 | 0.001 |
| Insufficient payload (model declined to judge) | 0.003 | 0.001 |
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 source (direct Gemma or distilled Codex), 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".