Abstract 297: Old Drug New Tricks: Repurposing Auranofin for Acute Myocardial Infarction by Targeting Protein Tyrosine Phosphatase PTP-PEST

Abstract

Rationale: Myocardial ischemia/reperfusion (I/R) injury is almost unavoidable since reperfusion is the only established treatment for acute myocardial infarction (AMI). To date there has no effective strategies available for reducing I/R injury. Objective: To elucidate the mechanisms underlying myocardial I/R injury and to develop new strategies for attenuating the damage it causes. Methods and Results: Using I/R-mice model created by ligation of left anterior descending (LAD) artery, we found increases in activity of protein tyrosine phosphatases (PTPs) in myocardium during I/R. Treating the I/R-mice with a pan-PTP inhibitor PVS (phenyl vinyl sulfone) attenuated I/R damage, suggesting PTPs activation to be harmful in I/R. Through analyzing myocardial RNAseq data, we showed PTPs that are abundantly expressed in the myocardium. By exposing cardiomyocytes ablated with specific endogenous PTPs to hypoxia/reoxygenation (H/R), we found a role that PTP-PEST (PTPn12) plays to promote cell death under H/R stress. Auranofin, a drug being used in clinical practice for treating rheumatoid arthritis, may target PTP-PEST thus suppressing its activity. We recapitulated the function of auranofin as a PTP-PEST inhibitor by in vitro studies, and then examined its effect on myocardial I/R injury. In the mice receiving auranofin before reperfusion, myocardial PTP activity was suppressed, leading to restored phosphorylation of PTP-PEST substrates, including ErbB-2 that maintains survival signaling of the heart. In line with the suppression of PTP-PEST activity, the auranofin-treated I/R-mice had smaller infarct size and better cardiac function. Conclusions: PTP-PEST contributes to part of the damages resulting from myocardial I/R. The PTP inhibitor auranofin, acting through the PTP-PEST-ErbB-2 signaling axis, reduces myocardial I/R injury. Based on the finding, auranofin could potentially be used in the development of treatments to manage I/R injury in patients with AMI.