Toll-like receptor 2 signaling triggers fatal arrhythmias upon myocardial ischemia–reperfusion*
Toll-like receptor 2 signaling triggers fatal arrhythmias upon myocardial ischemia–reperfusion*
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DOI：
10.1097/ccm.0b013e3181ef455b
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发表时间：
2010-10
影响因子：
8.8
通讯作者：
J. Mersmann;A. Koch;N. Tran;R. Zimmermann;T. Granja;J. Larmann;C. Herzog;G. Theilmeier;S. Bornstein;C. Kirschning;K. Zacharowski
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文献类型：
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作者：
J. Mersmann;A. Koch;N. Tran;R. Zimmermann;T. Granja;J. Larmann;C. Herzog;G. Theilmeier;S. Bornstein;C. Kirschning;K. Zacharowski
目的：缺血后心肌血流量的恢复触发了涉及Toll样受体的炎症反应。Toll样受体2缺陷与心肌缺血和再灌注后梗死面积减少相关。由于在C3 HeN野生型小鼠中观察到显著的死亡率，而在TLR 2 −/−小鼠中没有，我们测试了心律失常是否是潜在的病理学，并旨在阐明Toll样受体2结扎如何预防致命的心律失常。设计：实验动物模型。单位：大学医院研究实验室。对象：雄性C3 HeN小鼠。干预：通过结扎冠状动脉左前降支20分钟，然后再灌注24小时，手术诱导心肌缺血和再灌注。在观察期间通过植入式遥测发射器连续记录心电图，以检测再灌注期间的心律失常。测量和主要结果：心肌缺血和再灌注后，Toll样受体2表达与51%的死亡率（45只小鼠中有23只死亡）相关。缺乏toll样受体2使存活率提高至100%（17只小鼠中有17只存活）。清醒动物的心电图诊断和组织学分析显示，Toll样受体2信号传导的缺失防止了心肌缺血和再灌注后病理性心率震荡的形成，并与野生型心脏相比调节了缺血区域连接蛋白43阳性间隙连接的密度，表明心律失常是观察到的死亡率的根本原因。结论：本研究结果提示Toll样受体2是预防心肌缺血再灌注后致死性心肌病并发症的新靶点。
Objective:Restoration of myocardial blood flow after ischemia triggers an inflammatory response involving toll-like receptors. Toll-like receptor 2 deficiency is associated with a reduced infarct size after myocardial ischemia and reperfusion. Because a marked mortality was observed in C3HeN wild-type mice, which was absent in TLR2−/− mice, we tested whether cardiac arrhythmias are the underlying pathology and aimed to elucidate how toll-like receptor 2 ligation might prevent lethal arrhythmias. Design:Experimental animal model. Setting:University hospital research laboratory. Subjects:Male C3HeN mice. Interventions:Myocardial ischemia and reperfusion was surgically induced by ligation of the left anterior descending coronary artery for 20 mins followed by 24 hrs of reperfusion. Electrocardiography was continuously recorded during the observation period through an implantable telemetry transmitter to detect cardiac arrhythmias during reperfusion. Measurements and Main Results:Toll-like receptor 2 expression was associated with a 51% mortality rate (23 of 45 mice died) after myocardial ischemia and reperfusion. Absence of toll-like receptor 2 improved survival toward 100% (17 of 17 mice survived). Electrocardiography diagnostics in conscious animals and histologic analysis revealed that absence of toll-like receptor 2 signaling prevented the formation of pathologic heart rate turbulence after myocardial ischemia and reperfusion and modulated the density of connexin 43-positive gap junctions in the ischemic area compared with wild-type hearts, indicating arrhythmia as the cause underlying the observed mortality. Conclusions:The results presented here indicate toll-like receptor 2 as a novel target for the prevention of lethal arrhythmic complications after myocardial ischemia and reperfusion.