Methylation of the hippo signalling effector YAP by SETD7 drives myocardial ischemic injury
Notice bibliographique
Résumé
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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Comment cette classification a été obtenuedéplier
Prédiction machine sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Le volet Gemma est une étiquette directe du modèle pour chaque travail de la base, lue sur la notice réduite au titre. Le volet Codex est un classifieur appris des 10 348 étiquettes directes de Codex et calibré sur les taux pondérés de l'échantillon; les champs sans appui suffisant ne portent aucun appel Codex. Le mode candidate est l'union des deux volets; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont pas des étiquettes humaines.
Scores du classifieur distillé par catégorie (deux têtes)
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,000 | 0,000 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,000 | 0,000 |
| Bibliométrie | 0,000 | 0,000 |
| Études des sciences et des technologies | 0,000 | 0,000 |
| Communication savante | 0,000 | 0,000 |
| Science ouverte | 0,000 | 0,000 |
| Intégrité de la recherche | 0,000 | 0,001 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,003 | 0,001 |
Scores machine (provisoires)
Les deux têtes enseignantes du modèle étudiant, lues sur ce travail. Un score ordonne la base pour la relecture; il n'affirme jamais une catégorie, et le statut de validation accompagne chaque rangée tel quel.
Scores de référence d'un modèle non mature (critères de maturité non atteints, 7 itérations). Un score ordonne; il n'affirme jamais une catégorie.
score_only:v0-immature-baseline · tel quel depuis la passe de notation : score_only signifie que le nombre peut ordonner les travaux, et qu'aucune étiquette de catégorie n'en découleClassification
machine, non validéePrédiction automatique; un appel candidat d’une seule source (Gemma direct ou Codex distillé), pas un consensus.
Le détail, modèle par modèle et score par score, se trouve en fin de page sous « Comment cette classification a été obtenue ».