Soluble Urokinase Plasminogen Activator Receptor (suPAR) Promotes Cardioprotective Intracellular Signalling in Myocardial Ischaemia

Soluble urokinase Plasminogen Activator Receptor (suPAR) is an emerging biomarker of inflammation capable of predicting cardiovascular outcomes. However, the biological activity of suPAR on the heart is poorly understood. Potential cardiac intracellular signalling pathways triggered by suPAR were explored. Isolated Langendorff rat hearts undergoing global ischaemia received treatment with either suPAR infusion or perfusion buffer (controls). Proteins were extracted from hearts for each treatment group, and Troponin T in rat outflow perfusates following ischaemia were measured. The phosphorylation status of each kinase was characterised using a phospho-specific antibody and a ratio of phosphorylation to the total protein was calculated. Analysis between treatment groups was performed with unpaired t-test with Welch’s correction. Hearts receiving suPAR treatment after ischaemia showed a 1.4-fold increase in Akt phosphorylation, and a 1.6-fold increase in Akt phosphorylation if suPAR was given before ischaemia. The ratio of p-Akt/Akt was 1.83±0.14 (n=7) in the post-ischaemic suPAR treatment group vs 1.3±0.04 (n=6) in controls (p=0.007). Pre-ischaemic suPAR treatment gave a p-Akt/Akt ratio of 1.08±0.03 (n=8) vs 0.67±0.11 (n=5) in controls (p=0.01). Upstream signalling ERK1 and ERK2 phosphorylation also increased at 2.6-fold (p=0.009) and 1.9-fold (p=0.01), respectively, in suPAR treated heart vs controls. Finally, suPAR treated hearts obtained lower Troponin T values compared with controls after recovery from ischaemia (p<0.001). suPAR infusion promoted the phosphorylation of ERK and Akt kinases in isolated rat heart tissue and reduced related cardiac troponin release after a period of global no-flow ischaemia. These actions suggest that suPAR is a novel activator of the reperfusion injury salvage kinase (RISK) pathway.