Mastrocola Raffaella, Penna Claudia, Tullio Francesca, Femminò Saveria, Nigro Debora, Chiazza Fausto, Serpe Loredana, Collotta Debora, Alloatti Giuseppe, Cocco Mattia, Bertinaria Massimo, Pagliaro Pasquale, Aragno Manuela, Collino Massimo
Department of Clinical and Biological Sciences, University of Turin, Torino, Italy.
Department of Drug Science and Technology, University of Turin, Torino, Italy.
Oxid Med Cell Longev. 2016;2016:5271251. doi: 10.1155/2016/5271251. Epub 2016 Dec 8.
Although the nucleotide-binding oligomerization domain- (NOD-) like receptor pyrin domain containing 3 (NLRP3) inflammasome has been recently detected in the heart, its role in cardiac ischemia/reperfusion (IR) is still controversial. Here, we investigate whether a pharmacological modulation of NLRP3 inflammasome exerted protective effects in an model of IR injury. Isolated hearts from male Wistar rats (5-6 months old) underwent ischemia (30 min) followed by reperfusion (20 or 60 min) with and without pretreatment with the recently synthetized NLRP3 inflammasome inhibitor INF4E (50 M, 20 min before ischemia). INF4E exerted protection against myocardial IR, shown by a significant reduction in infarct size and lactate dehydrogenase release and improvement in postischemic left ventricular pressure. The formation of the NLRP3 inflammasome complex was induced by myocardial IR and attenuated by INF4E in a time-dependent way. Interestingly, the hearts of the INF4E-pretreated animals displayed a marked improvement of the protective RISK pathway and this effect was associated increase in expression of markers of mitochondrial oxidative phosphorylation. Our results demonstrate for the first time that INF4E protected against the IR-induced myocardial injury and dysfunction, by a mechanism that involves inhibition of the NLRP3 inflammasome, resulting in the activation of the prosurvival RISK pathway and improvement in mitochondrial function.
尽管核苷酸结合寡聚化结构域（NOD）样受体含吡啉结构域3（NLRP3）炎性小体最近已在心脏中被检测到，但其在心脏缺血/再灌注（IR）中的作用仍存在争议。在此，我们研究NLRP3炎性小体的药物调节是否能在IR损伤模型中发挥保护作用。雄性Wistar大鼠（5 - 6月龄）的离体心脏先经历缺血（30分钟），然后在有或没有用最近合成的NLRP3炎性小体抑制剂INF4E（50μM，缺血前20分钟）预处理的情况下进行再灌注（20或60分钟）。INF4E对心肌IR具有保护作用，表现为梗死面积和乳酸脱氢酶释放显著减少，以及缺血后左心室压力改善。NLRP3炎性小体复合物的形成由心肌IR诱导，并被INF4E以时间依赖性方式减弱。有趣的是，经INF4E预处理的动物心脏显示出保护性RISK通路的显著改善，并且这种作用与线粒体氧化磷酸化标志物表达增加有关。我们的结果首次证明，INF4E通过抑制NLRP3炎性小体的机制，保护心脏免受IR诱导的心肌损伤和功能障碍，从而导致促生存RISK通路的激活和线粒体功能的改善。
