Necrostatin‐1 alleviates reperfusion injury following acute myocardial infarction in pigs
S Koudstaal, MIFJ Oerlemans… - European journal of …, 2015 - Wiley Online Library
S Koudstaal, MIFJ Oerlemans, TIG Van der Spoel, AWF Janssen, IE Hoefer, PA Doevendans…
European journal of clinical investigation, 2015•Wiley Online LibraryBackground In rodents, it has previously been shown that necrostatin‐1 (Nec‐1) inhibits RIP
1, 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 (69±3 kg), I/R injury was induced by a 75‐min surgical ligation of the left …
1, 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 (69±3 kg), I/R injury was induced by a 75‐min surgical ligation of the left …
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 (69 ± 3 kg), 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 (1·0 mg/kg or 3·3 mg/kg) or vehicle treatment (control, CTRL). Functional endpoints and immunohistological analyses were performed 24 h after reperfusion.
Results
Nec‐1 3·3 mg/kg significantly reduced IS (n = 6; 24·4 ± 15·6%) compared to Nec‐1 1·0 mg/kg (n = 5; 54·8 ± 16·9%) or CTRLs (n = 6; 62·1 ± 26·6%; P = 0·016). In line, LV ejection fraction (LVEF) was significantly higher in Nec‐1 3·3 mg/kg, compared to Nec‐1 1·0 mg/kg or CTRL treated animals (50·0 ± 12·0% vs. 32·5 ± 12·9% vs. 31·9 ± 6·6%, respectively, P = 0·015). Hemodynamically, a preserved contractility was observed [end‐systolic volume at 100 mmHg (ESV100)] at 24‐h follow‐up (87·6 ± 17·3 mL vs. 74·5 ± 41·1 mL vs. 56·8 ± 11·8 mL, respectively, P = 0·032), 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.
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