Methylation of the Hippo effector YAP by the methyltransferase SETD7 drives myocardial ischaemic injury: a translational study. Issue 17 (16th June 2022)

• Record Type: Journal Article
• Authors: Ambrosini, Samuele; Montecucco, Fabrizio; Kolijn, Detmar; Pedicino, Daniela; Akhmedov, Alexander; Mohammed, Shafeeq A; Herwig, Melissa; Gorica, Era; Szabó, Petra L; Weber, Lukas; Russo, Giulio; Vinci, Ramona; Matter, Christian M; Liuzzo, Giovanna; Brown, Peter J; Rossi, Fabio M V; Camici, Giovanni G; Sciarretta, Sebastiano; Beltrami, Antonio P; Crea, Filippo; Podesser, Bruno; Lüscher, Thomas F; Kiss, Attila; Ruschitzka, Frank; Hamdani, Nazha; Costantino, Sarah; Paneni, Francesco
• Is Part Of: Cardiovascular research. Volume 118:Issue 17(2022)
• Page Start: 3374
• Page End: 3385
• Publication Date: 2022-06-16
• Subjects: Myocardial infarction -- Ischaemic heart disease -- Protein methylation -- Oxidative stress -- Hippo pathway; Cardiovascular system -- Diseases -- Periodicals; Cardiovascular system -- Periodicals; 616.1
• DOI: 10.1093/cvr/cvac102
• Languages: English
• ISSNs: 0008-6363

Abstract

Abstract: Aims: 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. The present study investigates the role of SETD7 in myocardial ischaemic injury. Methods and results: Experiments were performed in neonatal rat ventricular myocytes (NRVMs), SETD7 knockout mice ( SETD7 −/− ) undergoing myocardial ischaemia/reperfusion (I/R) injury, left ventricular (LV) myocardial samples from patients with ischaemic cardiomyopathy (ICM), and peripheral blood mononuclear cells (PBMCs) from patients with ST-elevation MI (STEMI). 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 manganese superoxide dismutase (MnSOD) and catalase (CAT). Such impairment of antioxidant defence was associated with mitochondrial reactive oxygen species (mtROS), organelle swelling, and apoptosis. Selective pharmacological inhibition of SETD7 by (R) -PFI-2 restored YAP nuclear localization, thus preventing mtROS, mitochondrial damage, and apoptosis in NRVMs. In mice, genetic deletion of SETD7 attenuated myocardial I/R injury, mtROS, and LV dysfunction by restoring YAP-dependent transcription of MnSOD and CAT. Moreover, in cardiomyocytes isolated from I/R mice and ICM patients, (R) -PFI-2 prevented mtROS accumulation, while improving Ca 2+ -activated tension. Finally, SETD7 was up-regulated in PBMCs from STEMI patients and negatively correlated with MnSOD and CAT. Conclusion: We show a methylation-dependent checkpoint regulating oxidative stress during myocardial ischaemia. SETD7 inhibition may represent a valid therapeutic strategy in this setting. Graphical Abstract: Graphical Abstract Schematic summarizing the main study findings. Myocardial ischaemia favours SETD7-dependent methylation of YAP, leading to its cytosolic retention and reduced transcription of antioxidant genes MnSOD and CAT. The reduction of antioxidant defence precipitates myocardial injury and cardiomyocyte dysfunction. In contrast, SETD7 inhibition prevents YAP methylation, thus promoting its nuclear localization and binding to the promoter of antioxidant genes. These events lead to the restoration of antioxidant defence with subsequent cardiac protection. MnSOD, manganese superoxide dismutase; CAT, catalase.