Vince C de Hoog1, Sandra M Bovens1, Saskia C A de Jager1, Ben J van Middelaar1, Amerik van Duijvenvoorde1, Pieter A Doevendans2, Gerard Pasterkamp3, Dominique P V de Kleijn4, Leo Timmers5. 1. Laboratory of Experimental Cardiology, UMC Utrecht, Room G02.523, Heidelberglaan 100, 3584 CX Utrecht, The Netherlands. 2. Department of Cardiology, UMC Utrecht, Utrecht, The Netherlands. 3. 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. 4. 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. 5. Laboratory of Experimental Cardiology, UMC Utrecht, Room G02.523, Heidelberglaan 100, 3584 CX Utrecht, The Netherlands Department of Cardiology, UMC Utrecht, Utrecht, The Netherlands.
Abstract
AIMS: 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. METHODS AND 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. CONCLUSION: 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. Published on behalf of the European Society of Cardiology. All rights reserved.
AIMS: 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 B4is 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. METHODS AND 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. CONCLUSION: 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. Published on behalf of the European Society of Cardiology. All rights reserved.
Authors: Guilielmus H J M Ellenbroek; Judith J de Haan; Bas R van Klarenbosch; Maike A D Brans; Sander M van de Weg; Mirjam B Smeets; Sanne de Jong; Fatih Arslan; Leo Timmers; Marie-José T H Goumans; Imo E Hoefer; Pieter A Doevendans; Gerard Pasterkamp; Linde Meyaard; Saskia C A de Jager Journal: Sci Rep Date: 2017-12-21 Impact factor: 4.379