Methyltransferase Setd7 Drives Myocardial Ischemic Injury By Modulating The Hippo Pathway: A Study In Mice And Humans

Introduction: Ischemic heart disease is a leading cause of death worldwide. Although revascularization strategies significantly reduce mortality after acute myocardial infarction (MI), a significant number of MI patients develop heart failure. Protein methylation is emerging as a key biological signal implicated in the pathophysiology of cardiovascular (CV) disease. In this regard, the methyltransferase SETD7 was recently shown to methylate proteins relevant to CV homeostasis. Hypothesis: To investigate SETD7 role in myocardial ischemia-reperfusion (I/R) injury. Methods: Experiments were performed in neonatal rat ventricular myocytes (NRVM), SETD7 knockout mice (SETD7 -/- ) undergoing myocardial I/R injury, myocardial samples from patients with and without ischemic heart failure as well as peripheral blood mononuclear cells from patients with ST elevation MI (STEMI, n=25) and age-matched healthy controls (n=20). Results: Glucose deprivation (GD) in NRVM led to upregulation of SETD7 and direct mono-methylation of the Hippo signaling effector YAP. SETD7-dependent methylation of YAP led to its cytosolic retention thus impeding YAP binding to the promoter of pro-survival genes. Selective pharmacological inhibition of SETD7 by (R)-PFI-2 blunted YAP mono-methylation thereby restoring its nuclear retention. We show that YAP binds the promoter of antioxidant genes catalase and superoxide dismutase, thus preventing GD-induced mitochondrial oxidative stress, organelle swelling and apoptosis. Consistently, infarct size, myocardial oxidative stress and left ventricular dysfunction were reduced in SETD7 -/- mice undergoing I/R as compared to wild-type littermates. Of clinical relevance, we found that SETD7/YAP signaling was deregulated in myocardial samples from patients with ischemic heart failure as well as in peripheral blood mononuclear cells from STEMI patients. Conclusions: We demonstrate that SETD7-dependent methylation of YAP is an important mechanism underpinning myocardial oxidative stress, mitochondrial damage and apoptosis during ischemia. Pharmacological modulation of SETD7 by (R)-PFI-2 may represent a potential therapeutic approach to prevent myocardial ischemic damage through modulation of the Hippo pathway.