Necrostatin-1 alleviates reperfusion injury following acute myocardial infarction in pigs

Abstract

Background In rodents, it has previously been shown that necrostatin-1 (Nec-1) inhibits RIP1, a central regulator of programmed necrosis, thereby decreasing cell death and reducing infarct size (IS) after ischaemia/reperfusion (I/R) injury. To address unanswered questions on feasibility and efficacy of Nec-1 in a large animal model, we assessed the effects of Nec-1 in a porcine I/R model, relevant to human disease. Materials and methods In Dalland landrace pigs (693kg), I/R injury was induced by a 75-min surgical ligation of the left circumflex coronary artery (LCx). Ten minutes prior to reperfusion, pigs were randomly allocated to different Nec-1 doses (10mg/kg or 33mg/kg) or vehicle treatment (control, CTRL). Functional endpoints and immunohistological analyses were performed 24h after reperfusion. Results Nec-1 33mg/kg significantly reduced IS (n=6; 244 +/- 156%) compared to Nec-1 10mg/kg (n=5; 548 +/- 169%) or CTRLs (n=6; 621 +/- 266%; P=0016). In line, LV ejection fraction (LVEF) was significantly higher in Nec-1 33mg/kg, compared to Nec-1 10mg/kg or CTRL treated animals (500 +/- 120% vs. 325 +/- 129% vs. 319 +/- 66%, respectively, P=0015). Hemodynamically, a preserved contractility was observed [end-systolic volume at 100mmHg (ESV100)] at 24-h follow-up (876 +/- 173mL vs. 745 +/- 411mL vs. 568 +/- 118mL, respectively, P=0032), reflecting improved cardiac function. Conclusions In the pig model of I/R injury, intravenous administration of Nec-1 prior to reperfusion was an effective and above all practical therapeutic strategy that significantly reduced IS and preserved left ventricular function. These data highlight the potential of cardioprotection as a promising adjuvant therapy in the setting of early reperfusion following I/R injury.