Targeting the methyltransferase setd7 prevents myocardial ischemic injury: a translational study
| Autor: | S Ambrosini, F Montecucco, D Kolijn, A Akhmedov, D Pedicino, S Mohammed, A Kiss, A Beltrami, F Crea, T Luescher, N Hamdani, S Costantino, F Paneni |
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| Rok vydání: | 2021 |
| Předmět: | |
| Zdroj: | European Heart Journal. 42 |
| ISSN: | 1522-9645 0195-668X |
| DOI: | 10.1093/eurheartj/ehab724.3252 |
| Popis: | Background Despite appropriate revascularization strategies, a significant number of patients with myocardial infarction (MI) develop ischemic heart failure suggesting that breakthrough therapies are yet to be approved in this setting. Methylation of non-histone proteins is emerging as a central regulatory mechanism in health and disease. The methyltransferase SETD7 has shown to methylate and alter the function of a variety of proteins in vitro, however its function in the heart is poorly understood. Purpose In the present study we sought to determine the role of SETD7 in myocardial ischemic injury. Methods Neonatal rat ventricular myocytes (NRVM) were exposed to 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 and oxidative stress were assessed by Caspase-3 activity assay and mitochondrial swelling. YAP activity was assessed through chromatin immunoprecipitation assay (ChIP), its localization was examined by confocal microscopy while mono-methylation was assessed by immunoblotting. Expression of YAP-dependent antioxidant genes was assessed by western blot. SETD7 knockout (SETD7−/−) mice and wild-type (WT) littermates underwent ischemia/reperfusion (I/R) injury. Rats underwent permanent ligation of left anterior descending coronary artery (MI). Left ventricular (LV) myocardial samples were collected from mice undergoing I/R injury and patients with ischemic cardiomyopathy (ICM) and treated ex-vivo with (R)-PFI-2. SETD7 and antioxidant genes expression was assessed in peripheral blood mononuclear cells (PBMCs) from patients with ST-elevation MI (STEMI). Results We show that SETD7 is activated upon energy deprivation in cultured NRVMs and methylates the Hippo pathway effector YAP, leading to its cytosolic retention and impaired transcription of antioxidant genes. Pharmacological inhibition of SETD7 by (R)-PFI-2 restored YAP nuclear localization thus preventing mitochondrial reactive oxygen species (mtROS) and apoptosis. SETD7 deletion in mice attenuated I/R injury, mtROS and LV dysfunction by restoring YAP-dependent transcriptional programs. SETD7/YAP dysregulation was also observed in rats with MI and LV specimens from ICM patients. Of note, (R)-PFI-2 treatment prevented titin oxidation and myofilament stiffness in cardiomyocytes isolated from I/R mice and patients with ICM. Finally, SETD7 was upregulated in STEMI patients and its expression negatively correlated with antioxidant genes. Conclusions Targeting SETD7 may represent a valid therapeutic strategy to protect the heart during ischemia. Funding Acknowledgement Type of funding sources: Public Institution(s). Main funding source(s): University of Zurich |
| Databáze: | OpenAIRE |
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