title: BLT1 antagonist LSN2792613 reduces infarct size in a mouse model of myocardial ischaemia-reperfusion injury.
abstract: OBJECTIVE
  Restoration of coronary blood flow is crucial in the treatment of acute myocardial infarction. Reperfusion, however, induces ischaemia-reperfusion (IR) injury, which further deteriorates myocardial function. The innate immune system plays an important role in this process, mediating rapid influx of immune cells into the reperfused myocardium. Leukotriene B4 is an important leucocyte chemoattractant, performing its actions through binding to its specific receptor BLT1. We hypothesized that treatment with LSN2792613, a selective BLT1 antagonist, reduces infarct size (IS) in a mouse model of myocardial IR injury.
  
  
  RESULTS
  Male C57Bl/6J mice were subjected to myocardial ischaemia for 30 min by surgical coronary artery ligation, followed by reperfusion. Mice received either LSN2792613 or vehicle, three times daily (orally) for up to 72 h after reperfusion. BLT1 inhibition with LSN2792613 reduced IS compared with vehicle treatment (26.9 ± 2.7 vs. 34.9 ± 2.2%, P = 0.030) at 24 h after reperfusion. The levels of IL-6 and keratinocyte chemoattractant were reduced in the infarcted tissue of LSN2792613-treated mice. Reduced apoptosis in LSN2792613-treated mice was suggested by increased levels of phosphorylated JNK and GSK3α/β, and confirmed by flow cytometric analysis showing less apoptotic and necrotic cardiomyocytes in the infarcted myocardium. Echocardiography at 4 weeks after myocardial IR showed a slightly higher ejection fraction and stroke volume in mice treated with LSN2792613 compared with vehicle-treated mice, whereas left ventricular volumes were comparable.
  
  
  CONCLUSIONS
  Selective BLT1 inhibition with LSN2792613 reduces inflammation and apoptosis following IR, resulting in reduced IS, and therefore might be a promising strategy to prevent myocardial IR injury.
authors.affiliation: Laboratory of Experimental Cardiology, UMC Utrecht, Room G02.523, Heidelberglaan 100, 3584 CX Utrecht, The Netherlands.
authors.forename: Vince C
authors.initials: VC
authors.lastname: de Hoog
authors.affiliation: Laboratory of Experimental Cardiology, UMC Utrecht, Room G02.523, Heidelberglaan 100, 3584 CX Utrecht, The Netherlands.
authors.forename: Sandra M
authors.initials: SM
authors.lastname: Bovens
authors.affiliation: Laboratory of Experimental Cardiology, UMC Utrecht, Room G02.523, Heidelberglaan 100, 3584 CX Utrecht, The Netherlands.
authors.forename: Saskia C A
authors.initials: SC
authors.lastname: de Jager
authors.affiliation: Laboratory of Experimental Cardiology, UMC Utrecht, Room G02.523, Heidelberglaan 100, 3584 CX Utrecht, The Netherlands.
authors.forename: Ben J
authors.initials: BJ
authors.lastname: van Middelaar
authors.affiliation: Laboratory of Experimental Cardiology, UMC Utrecht, Room G02.523, Heidelberglaan 100, 3584 CX Utrecht, The Netherlands.
authors.forename: Amerik
authors.initials: A
authors.lastname: van Duijvenvoorde
authors.affiliation: Department of Cardiology, UMC Utrecht, Utrecht, The Netherlands.
authors.forename: Pieter A
authors.initials: PA
authors.lastname: Doevendans
authors.affiliation: Laboratory of Experimental Cardiology, UMC Utrecht, Room G02.523, Heidelberglaan 100, 3584 CX Utrecht, The Netherlands Department of Clinical Chemistry and Haematology, UMC Utrecht, Utrecht, The Netherlands.
authors.forename: Gerard
authors.initials: G
authors.lastname: Pasterkamp
authors.affiliation: Laboratory of Experimental Cardiology, UMC Utrecht, Room G02.523, Heidelberglaan 100, 3584 CX Utrecht, The Netherlands ICIN - Netherlands Heart Institute, Utrecht, The Netherlands Surgery NUS and Cardiovascular Research Institute, NUHS, Singapore surdvp@nus.edu.sg.
authors.forename: Dominique P V
authors.initials: DP
authors.lastname: de Kleijn
authors.affiliation: Laboratory of Experimental Cardiology, UMC Utrecht, Room G02.523, Heidelberglaan 100, 3584 CX Utrecht, The Netherlands Department of Cardiology, UMC Utrecht, Utrecht, The Netherlands.
authors.forename: Leo
authors.initials: L
authors.lastname: Timmers
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002316:Cardiotonic Agents / Q000494:pharmacology*; D003094:Collagen / Q000378:metabolism; D019610:Cytoprotection; D004195:Disease Models, Animal; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D015850:Interleukin-6 / Q000378:metabolism; D016209:Interleukin-8 / Q000378:metabolism; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D020024:Leukotriene Antagonists / Q000494:pharmacology*; D008297:Male; D008810:Mice, Inbred C57BL; D009203:Myocardial Infarction / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D015428:Myocardial Reperfusion Injury / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D009336:Necrosis; D010766:Phosphorylation; D018102:Receptors, Leukotriene B4 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013318:Stroke Volume / Q000187:drug effects; D013997:Time Factors; D016277:Ventricular Function, Left / Q000187:drug effects; D020257:Ventricular Remodeling / Q000187:drug effects
chemical_list: D000893:Anti-Inflammatory Agents; D002316:Cardiotonic Agents; D015850:Interleukin-6; D016209:Interleukin-8; D020024:Leukotriene Antagonists; C503704:Ltb4r1 protein, mouse; D018102:Receptors, Leukotriene B4; C577686:interleukin-6, mouse; D003094:Collagen; D000071679:Glycogen Synthase Kinase 3 beta; D048031:JNK Mitogen-Activated Protein Kinases; D038362:Glycogen Synthase Kinase 3; C448021:glycogen synthase kinase 3 alpha
keywords: BLT1; Ischaemia–reperfusion; LTB4; Leukotriene; Myocardial infarction