Targeting protein tyrosine phosphatase PTP-PEST (PTPN12) for therapeutic intervention in acute myocardial infarction. Issue 5 (22nd June 2019)

• Record Type: Journal Article
• Authors: Yang, Chiu-Fen; Chen, Yi-Yun; Singh, Jai Prakash; Hsu, Shu-Fang; Liu, Yu-Wen; Yang, Chun-Yi; Chang, Chia-Wei; Chen, Szu-Ni; Shih, Rou-Ho; Hsu, Shang-Te Danny; Jou, Yuh-Shan; Cheng, Ching-Feng; Meng, Tzu-Ching
• Is Part Of: Cardiovascular research. Volume 116:Issue 5(2020)
• Page Start: 1032
• Page End: 1046
• Publication Date: 2019-06-22
• Subjects: Protein tyrosine phosphatase -- Acute myocardial infarction -- Ischaemia/reperfusion injury; Cardiovascular system -- Diseases -- Periodicals; Cardiovascular system -- Periodicals; 616.1
• DOI: 10.1093/cvr/cvz165
• Languages: English
• ISSNs: 0008-6363

Abstract

Abstract: Aims: 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. Methods and results: 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. 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 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. Graphical Abstract: