Abstract 149: Targeting Protein Tyrosine Phosphatase PTP-PEST for Therapeutic Interventions in Acute Myocardial Infarction

Abstract

Introduction: To date reperfusion remains the only established clinical management to salvage ischemic myocardium. However, reperfusion also results in additional damage. New interventions that prevent myocardial injury caused by ischemia/reperfusion (I/R) are the unmet clinical need. A hallmark of I/R-induced cardiac signaling perturbation is dysregulation of protein tyrosine phosphorylation (pTyr), which is dynamically controlled by protein tyrosine phosphatases (PTPs) and protein tyrosine kinases (PTKs). Recent works showed that forced activation of myocardial PTKs reduces I/R injury to the heart, suggesting a detrimental effect of protein tyrosine dephosphorylation by PTPs on the survival of myocardium. However, the role of PTPs in this disease context has never been explored. Hypothesis: PTPs may act to promote I/R-induced injury to the heart. Methods: Mice received the surgery for myocardial ischemia (1 h) followed by reperfusion (4 h). We measured the myocardial PTP activity, the pTyr level of cardiac proteins, and the degree of heart injury. To suppress endogenous PTP activity, mice were treated with phenyl vinyl sulfone (PVS), a pan-PTP inhibitor. Results: We found that the overall myocardial PTP activity was significantly elevated after ischemia and I/R, in line with a decrease of pTyr in cardiac proteins. Interestingly, PTP-PEST, which is abundantly expressed in myocardium, underwent protease-processed activation in the heart exposed to I/R. Consistently, the pTyr of paxillin and p130CAS, both which are the substrates of PTP-PEST, was significantly diminished. Treatment of the mice with PVS, an inhibitor that inactivates PTP-PEST, protected the heart from I/R injury. Conclusion: Our finding suggests that PTP-PEST may be a new target against myocardial I/R injury. The current focus is to validate the role of PTP-PEST in cardiac I/R damage and to test the therapeutic effect of drugable PTP-PEST inhibitors. New pharmacological interventions may be designed for improving the outcome of myocardial infarction.