Department of Cardiology, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, 707 Chung-Yang Road Sec. 3, Hualien 970, Taiwan.
Doctoral Degree Program in Translational Medicine, Tzu Chi University and Academia Sinica.
Cardiovasc Res. 2020 Apr 1;116(5):1032-1046. doi: 10.1093/cvr/cvz165.
The myocardial ischaemia/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.
Using a mouse model established by ligation of left anterior descending 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 attenuated I/R damage, suggesting PTP activation to be harmful in I/R. Through analysing 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 signalling 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.
PTP-PEST contributes to part of the damages resulting from myocardial I/R. The drug Auranofin, potentially acting through the PTP-PEST-ErbB-2 signalling 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.
再灌注是急性心肌梗死（AMI）唯一确立的治疗方法，因此心肌缺血/再灌注（I/R）损伤几乎是不可避免的。迄今为止，尚无有效的策略可用于减少 I/R 损伤。我们的目的是阐明心肌 I/R 损伤的机制，并开发一种减轻其损伤的新策略。
我们使用结扎左前降支建立的小鼠模型，发现 I/R 期间心肌中蛋白酪氨酸磷酸酶（PTP）的活性增加。用泛 PTP 抑制剂苯乙烯磺酰氟（phenyl vinyl sulfone）治疗 I/R 小鼠可减轻 I/R 损伤，表明 PTP 激活在 I/R 中是有害的。通过分析 RNAseq 数据，我们表明 PTP 在小鼠心肌中大量表达。通过用 RNAi 使内源性 PTP 缺失的原代心肌细胞暴露于缺氧/复氧（H/R），我们发现 PTP-PEST（PTPN12）在 H/R 应激下促进细胞死亡的作用。金诺芬（Auranofin）是一种用于治疗类风湿关节炎的临床药物，可能靶向 PTP-PEST 从而抑制其活性。我们通过结构研究阐明了金诺芬诱导的 PTP-PEST 失活的分子基础，然后检查了其对心肌 I/R 损伤的影响。在再灌注前给予金诺芬的小鼠中，心肌 PTP 活性受到抑制，导致 PTP-PEST 底物，包括维持心脏存活信号的 ErbB-2 的磷酸化恢复。与 PTP-PEST 活性抑制一致，金诺芬处理的 I/R 小鼠的梗死面积较小，心功能较好。
PTP-PEST 导致部分心肌 I/R 损伤。金诺芬（Auranofin）可能通过 PTP-PEST-ErbB-2 信号轴发挥作用，可减少心肌 I/R 损伤。基于这一发现，金诺芬可用于开发新的治疗方法，以管理 AMI 患者的 I/R 损伤。
