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

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.

Identification of Common Mechanisms and Key Genes in the Chronic Obstructive Pulmonary Disease and Acute Myocardial Infarction

“…The mRNA expression of ERBB2 receptors was signi cantly down-regulated in the left ventricle of MI compared with the normal left ventricle [25]. PTP-PEST contributed to part of the damages resulting from myocardial I/R and Aurano n, potentially acting through the PTP-PEST-ERBB2 signalling axis, reduced myocardial I/R injury [61]. S100 proteins are Ca 2 +-binding proteins exclusively expressed in vertebrates in a cell-speci c manner and they might regulate a variety of functions acting as intracellular Ca 2 + sensors transducing the Ca 2 + signal and extracellular factors affecting cellular activity via ligation of a battery of membrane receptors [62].…”

Microbially guided discovery and biosynthesis of biologically active natural products

“…We explored the versatility of our B2H system by assessing its ability to detect the inactivation of several other disease-relevant PTPs. In short, we swapped out the gene for PTP1B with genes for PTPN2, PTPN6, or PTPN12; these enzymes are targets for immunotherapeutic enhancement 59 , the treatment of ovarian cancer 60 , and acute myocardial infarction 61 , respectively.…”

Chronic inflammatory diseases, myocardial function and cardioprotection

“…Concerning glucocorticoids in systemic lupus erythematosus, evidence is more straightforward showing deleterious side effects in heart and vessels (Wu et al, 2016) and clinicians agree in minimizing or withdrawing glucocorticoid dosage whenever it is possible (Fanouriakis et al, 2019 (Au et al, 2011;Chu et al, 2013;Derk & Jimenez, 2007;Spethman et al, 2014;Ungprasert et al, 2014). In parallel, they exhibit significant microvascular dysfunction (MVD) which is responsible for multiple manifestations of this disease, such as Raynaud phenomenon, pulmonary artery hypertension or renal sclerosis (Faccini, Kaski, & Camici, 2016).…”

“…Very recently, it has been demonstrated that Auranofin, a drug being used in clinical practice for treating rheumatoid arthritis reduces infarct size and results in better cardiac function when it is administered in mice before reperfusion. The potential underlying mechanism may involve the protein tyrosine phosphatases (PTP)‐PEST‐ErbB‐2 signalling axis (Yang et al, 2019). In a mouse model of adjuvant‐induced arthritis, which mimics RA in humans, ischaemic preconditioning did not result in a significant reduction of myocardial necrosis area induced by 30 min of ischaemia and 60 min of reperfusion (Wojciechowska et al, 2013).…”