Targeting protein tyrosine phosphatase PTP-PEST (PTPN12) for therapeutic intervention in acute myocardial infarction

Cardiovasc Res. 2020 Apr 1;116(5):1032-1046. doi: 10.1093/cvr/cvz165.

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.

Keywords: Acute myocardial infarction•; Ischaemia/reperfusion injury; Protein tyrosine phosphatase•.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Auranofin / pharmacology*
  • Cell Hypoxia
  • Cell Line
  • Disease Models, Animal
  • Enzyme Activation
  • Enzyme Inhibitors / pharmacology*
  • Male
  • Mice, Inbred C57BL
  • Molecular Targeted Therapy
  • Myocardial Infarction / enzymology
  • Myocardial Infarction / pathology
  • Myocardial Infarction / physiopathology
  • Myocardial Infarction / prevention & control*
  • Myocardial Reperfusion Injury / enzymology
  • Myocardial Reperfusion Injury / pathology
  • Myocardial Reperfusion Injury / physiopathology
  • Myocardial Reperfusion Injury / prevention & control*
  • Myocytes, Cardiac / drug effects*
  • Myocytes, Cardiac / enzymology
  • Myocytes, Cardiac / pathology
  • Protein Tyrosine Phosphatase, Non-Receptor Type 12 / antagonists & inhibitors*
  • Protein Tyrosine Phosphatase, Non-Receptor Type 12 / genetics
  • Protein Tyrosine Phosphatase, Non-Receptor Type 12 / metabolism
  • Rats
  • Receptor, ErbB-2 / metabolism
  • Signal Transduction

Substances

  • Enzyme Inhibitors
  • Auranofin
  • Erbb2 protein, mouse
  • Receptor, ErbB-2
  • PTPN12 protein, human
  • Protein Tyrosine Phosphatase, Non-Receptor Type 12
  • Ptpn12 protein, mouse