Cardioprotection by soluble urokinase plasminogen activator receptor (suPAR) in an in vivo model of myocardial infarction with ischaemia-reperfusion
J Chew-Harris, T Pirker, M Byers, X Wu, R Gourdier, C Charles, A M Richards, T Pham, P Adamson, C PembertonAbstract
Aims
Soluble urokinase plasminogen activator receptor (suPAR) has demonstrated cardioprotective effects in an ex vivo model of myocardial ischaemia, but its effects in vivo during ischaemia-reperfusion injury remain unclear. This study assessed suPAR’s therapeutic potential in a small animal model of myocardial infarction (MI) with ischaemia-reperfusion.
Methods
A left anterior descending coronary artery occlusion for 60 minutes was conducted on 10–12-week-old Sprague-Dawley rats, followed by reperfusion, and recovery to 2 days post-MI. Animals were randomised to receive suPAR or saline via intravenous bolus injection 5 minutes before reperfusion. Cardiac function was assessed at baseline pre-MI and again at 48 hours post-MI using transthoracic echocardiography (Phillips, iE33). Myocardial injury was quantified by serial cardiac troponin I at 4-, 24- and 48 hours (Abbott) and endpoint high-sensitivity Troponin T (Roche). At termination, cardiac tissue was harvested, formalin-fixed, and sectioned into the basal, mid-cavity, apical and apex regions. Histology of infarct size and immune infiltration was conducted using haematoxylin and eosin staining with subsequent quantification using a colour-based semi-automated algorithm, and apoptosis by TUNEL.
Results
At 48 hours post-MI, rats treated with suPAR (n=16) demonstrated markedly preserved cardiac function compared with controls (n=16). suPAR-treated animals showed significantly higher left ventricular ejection fraction (p=0.02), fractional shortening (p=0.005), and stroke volume (p=0.03). Cardiac troponin concentrations were substantially lower in the suPAR group, with reductions of 58% in serial sampling and 70% at endpoint (p=0.0003) (i.e. mean hscTnT= 400 ng/L (95%CI: 250-540) in the suPAR group versus 1320 ng/L (840-1800) in controls). Histological assessment confirmed a 76% mean reduction in infarcted area at the apex and a 57% reduction across the apical region (p=0.04). Immune cell infiltration surrounding infarcted tissue decreased by at least 30% (p=0.03), and TUNEL-positive cells were reduced by more than 50% in suPAR-treated hearts (p=0.01).
Conclusion
Our study reveals the first evidence of suPAR’s cardioprotection in vivo MI, reducing myocardial injury, preserving cardiac function, decreasing inflammatory response and cell death. These findings support suPAR as a promising therapeutic candidate for ischemic heart disease and warrant further ongoing research.