Chiu-Fen Yang1,2,3, Yi-Yun Chen3, Jai Prakash Singh3,4,5, Shu-Fang Hsu3, Yu-Wen Liu3, Chun-Yi Yang3,6, Chia-Wei Chang3, Szu-Ni Chen3, Rou-Ho Shih7, Shang-Te Danny Hsu3,4,6, Yuh-Shan Jou7, Ching-Feng Cheng2,7,8, Tzu-Ching Meng3,4,6. 1. Department of Cardiology, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, 707 Chung-Yang Road Sec. 3, Hualien 970, Taiwan. 2. Doctoral Degree Program in Translational Medicine, Tzu Chi University and Academia Sinica. 3. Institute of Biological Chemistry, Academia Sinica, 128 Academia Road Sec. 2, Nankang, Taipei 115, Taiwan. 4. Chemical Biology and Molecular Biophysics, Taiwan International Graduate program, Academia Sinica, 128 Academia Road Sec. 2, Nankang, Taipei 115, Taiwan. 5. Institute of Chemistry, National Tsing-Hua University, 101 Kuang-Fu Road Sec. 2, Hsinchu 300, Taiwan. 6. Institute of Biochemical Sciences, National Taiwan University, 1 Roosevelt Road Sec. 4, Taipei 106, Taiwan. 7. Institute of Biomedical Sciences, Academia Sinica, 128 Academia Road Sec. 2, Nankang, Taipei 115, Taiwan. 8. Department of Pediatrics, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, 289 Jianguo Road, Xindian Dist., New Taipei City 231, Taiwan.
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. Published on behalf of the European Society of Cardiology. All rights reserved.
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. Published on behalf of the European Society of Cardiology. All rights reserved.