Targeting the Methyltransferase Setd7 Prevents Myocardial Ischemic Injury: A Translational Study

Introduction: 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. Hypothesis: In the present study we sought to determine the role of SETD7 in myocardial ischemic injury. Methods: Experiments were performed in neonatal rat ventricular myocytes (NRVM), SETD7 knockout mice (SETD7-/-) undergoing myocardial ischemia/reperfusion (I/R) injury, rats undergoing permanent left anterior descending (LAD) artery ligation, myocardial samples from patients with and without ischemic cardiomyopathy (ICM) as well as peripheral blood mononuclear cells from patients with ST elevation MI (STEMI) and age-matched healthy controls. 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 permanent LAD ligation 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: In the present study we show that SETD7-dependent methylation of YAP is required for its inactivation, thus leading to myocyte oxidative stress and apoptosis. Therefore, we identified SETD7 as a valid and druggable therapeutic target to protect the heart during ischemia.