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 Ca2+-activated tension. Finally, SETD7 was up-regulated in PBMCs from STEMI patients and negatively correlated with MnSOD and CAT.

Methylation of the Hippo effector YAP by the methyltransferase SETD7 drives myocardial ischaemic injury. A translational study / Ambrosini, S.; Montecucco, F.; Kolijn, D.; Pedicino, D.; Akhmedov, A.; Mohammed, S. A.; Herwig, M.; Gorica, E.; Szabo, P. L.; Weber, L.; Russo, G.; Vinci, R.; Matter, C. M.; Liuzzo, G.; Brown, P. J.; Rossi, F. M. V.; Camici, G. G.; Sciarretta, S.; Beltrami, A. P.; Crea, F.; Podesser, B.; Luscher, T. F.; Kiss, A.; Ruschitzka, F.; Hamdani, N.; Costantino, S.; Paneni, F.. - In: CARDIOVASCULAR RESEARCH. - ISSN 0008-6363. - 118:17(2022), pp. 3374-3385. [10.1093/cvr/cvac102]

Methylation of the Hippo effector YAP by the methyltransferase SETD7 drives myocardial ischaemic injury. A translational study

Sciarretta S.;Paneni F.
2022

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 Ca2+-activated tension. Finally, SETD7 was up-regulated in PBMCs from STEMI patients and negatively correlated with MnSOD and CAT.
2022
Hippo pathway; ischaemic heart disease; myocardial infarction; oxidative stress; protein methylation
01 Pubblicazione su rivista::01a Articolo in rivista
Methylation of the Hippo effector YAP by the methyltransferase SETD7 drives myocardial ischaemic injury. A translational study / Ambrosini, S.; Montecucco, F.; Kolijn, D.; Pedicino, D.; Akhmedov, A.; Mohammed, S. A.; Herwig, M.; Gorica, E.; Szabo, P. L.; Weber, L.; Russo, G.; Vinci, R.; Matter, C. M.; Liuzzo, G.; Brown, P. J.; Rossi, F. M. V.; Camici, G. G.; Sciarretta, S.; Beltrami, A. P.; Crea, F.; Podesser, B.; Luscher, T. F.; Kiss, A.; Ruschitzka, F.; Hamdani, N.; Costantino, S.; Paneni, F.. - In: CARDIOVASCULAR RESEARCH. - ISSN 0008-6363. - 118:17(2022), pp. 3374-3385. [10.1093/cvr/cvac102]
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11573/1687801
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