AIMS The myocardial ischemia/reperfusion (I/R) injury is almost inevitable since reperfusion is the only established treatment for acute myocardial infarction (AMI). To date there is no effective strategy available for reducing the I/R injury. Our aim was to elucidate the mechanisms underlying myocardial I/R injury and to develop a new strategy for attenuating the damage it causes. METHODS AND RESULTS Using a mouse model established by ligation of left anterior descending (LAD) artery, we found an increase in activity of protein tyrosine phosphatases (PTPs) in myocardium during I/R. Treating the I/R-mice with a pan-PTP inhibitor phenyl vinyl sulfone (PVS) attenuated I/R damage, suggesting PTP activation to be harmful in I/R. Through analyzing RNAseq data, we showed PTPs being abundantly expressed in mouse myocardium. By exposing primary cardiomyocytes ablated with specific endogenous PTPs by RNAi 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 elucidated the molecular basis for Auranofin-induced inactivation of PTP-PEST by structural 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 the survival signaling of the heart. In line with the inhibition 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 drug Auranofin, potentially acting through the PTP-PEST-ErbB-2 signaling axis, reduces myocardial I/R injury. Based on this finding, Auranofin could be used in the development of new treatments that manage I/R injury in patients with AMI. TRANSLATIONAL PERSPECTIVE Cardiac ischemia/reperfusion (I/R) injury remains a significant health concern worldwide. A novel intervention for attenuating this detrimental effect is an unmet clinical need. Our study elucidates the role that protein tyrosine phosphatase PTP-PEST plays in promoting cardiac I/R injury. Auranofin, which is a FDA-approved drug, can inhibit the activity of PTP-PEST, leading to protection of the heart under I/R stress. These findings suggest the potential that Auranofin is holding to treat patients suffering acute myocardial infarction.

中文翻译：

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靶向蛋白酪氨酸磷酸酶PTP-PEST用于急性心肌梗死的治疗干预。

目的心肌缺血/再灌注（I / R）损伤几乎是不可避免的，因为再灌注是急性心肌梗死（AMI）的唯一公认治疗方法。迄今为止，还没有有效的策略可以减少I / R伤害。我们的目的是阐明心肌I / R损伤的潜在机制，并开发出减轻其造成的损害的新策略。方法和结果使用通过左前降支（LAD）动脉结扎建立的小鼠模型，我们发现I / R期间心肌蛋白酪氨酸磷酸酶（PTP）的活性增加。用泛PTP抑制剂苯基乙烯基砜（PVS）处理I / R小鼠可减轻I / R损伤，表明PTP激活对I / R有害。通过分析RNAseq数据，我们显示PTP在小鼠心肌中大量表达。通过将被RNAi特异性内源性PTP消融的原代心肌细胞暴露于缺氧/复氧（H / R），我们发现PTP-PEST（PTPN12）在促进H / R胁迫下促进细胞死亡的作用。临床实践中用于治疗类风湿关节炎的药物金诺芬可靶向PTP-PEST，从而抑制其活性。我们通过结构研究阐明了金刚霉素诱导的PTP-PEST失活的分子基础，然后研究了其对心肌I / R损伤的影响。在再灌注前接受金诺芬的小鼠中，心肌PTP活性被抑制，导致PTP-PEST底物（包括维持心脏存活信号的ErbB-2）恢复磷酸化。与抑制PTP-PEST活性一致，金诺芬治疗的I / R小鼠的梗死面积更小，心脏功能更好。结论PTP-PEST造成了心肌I / R造成的部分损害。可能通过PTP-PEST-ErbB-2信号轴起作用的药物金诺芬可减少心肌I / R损伤。基于这一发现，金诺芬可用于开发治疗AMI患者I / R损伤的新疗法。翻译的角度心脏缺血/再灌注（I / R）损伤在世界范围内仍然是重要的健康问题。减轻这种有害作用的新颖干预是尚未满足的临床需求。我们的研究阐明了蛋白酪氨酸磷酸酶PTP-PEST在促进心脏I / R损伤中的作用。Auranofin是FDA批准的药物，可以抑制PTP-PEST的活性，从而在I / R压力下保护心脏。