title: 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.
  
  
  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, copared 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.
authors.affiliation: Department of Cardiology, Division Heart and Lungs, University Medical Center Utrecht, Utrecht, the Netherlands; Interuniversity Cardiology Institute of the Netherlands (ICIN), Utrecht, the Netherlands.
authors.forename: Stefan
authors.initials: S
authors.lastname: Koudstaal
authors.forename: Martinus I F J
authors.initials: MI
authors.lastname: Oerlemans
authors.forename: Tycho I G
authors.initials: TI
authors.lastname: Van der Spoel
authors.forename: Aafke W F
authors.initials: AW
authors.lastname: Janssen
authors.forename: Imo E
authors.initials: IE
authors.lastname: Hoefer
authors.forename: Pieter A
authors.initials: PA
authors.lastname: Doevendans
authors.forename: Joost P G
authors.initials: JP
authors.lastname: Sluijter
authors.forename: Steven A J
authors.initials: SA
authors.lastname: Chamuleau
mesh_terms: D000818:Animals; D002316:Cardiotonic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D003331:Coronary Vessels; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004452:Echocardiography; D005260:Female; D006439:Hemodynamics / Q000187:drug effects; D007093:Imidazoles / Q000008:administration & dosage / Q000494:pharmacology*; D007211:Indoles / Q000008:administration & dosage / Q000494:pharmacology*; D007262:Infusions, Intravenous; D008026:Ligation; D009203:Myocardial Infarction / Q000503:physiopathology*; D015428:Myocardial Reperfusion Injury / Q000503:physiopathology / Q000517:prevention & control*; D009504:Neutrophils / Q000187:drug effects; D018384:Oxidative Stress / Q000187:drug effects; D011897:Random Allocation; D034421:Sus scrofa; D013552:Swine
chemical_list: D002316:Cardiotonic Agents; D007093:Imidazoles; D007211:Indoles; C507699:necrostatin-1
keywords: Cardioprotection; Nec-1; myocardial infarction; reperfusion injury