Attenuation of Myocardial Injury by HMGB1 Blockade during Ischemia/Reperfusion Is Toll-Like Receptor 2-Dependent
Attenuation of Myocardial Injury by HMGB1 Blockade during Ischemia/Reperfusion Is Toll-Like Receptor 2-Dependent
复制标题
DOI：
10.1155/2013/174168
复制
发表时间：
2013-01-01
影响因子：
4.6
通讯作者：
Koch, Alexander
中科院分区：
文献类型：
--
作者：
Mersmann, Jan;Iskandar, Franziska;Koch, Alexander
Toll样受体2（TLR 2）的基因或药物消融可防止心肌缺血/再灌注损伤（MI/R）。然而，负责TLR 2激活的内源性配体尚未被检测到。本研究的目的是鉴定HMGB 1作为MI/R期间TLR 2信号传导的激活剂。在心肌缺血（30分钟）和再灌注（24小时）前1小时，向C57 BL/6野生型（WT）或TLR 2（-/-）小鼠注射媒介物、HMGB 1或HMGB 1 BoxA。定量分析病灶大小、心肌肌钙蛋白T、白细胞浸润、HMGB 1释放、TLR 4-、TLR 9-和RAGE-表达。在接受冠状动脉旁路移植术（CABG）手术的患者中测量HMGB 1血浆水平。HMGB 1拮抗剂BoxA减少WT小鼠MI/R期间的心肌细胞坏死，同时伴有白细胞浸润减少。然而，注射HMGB 1并没有增加WT动物的梗死面积。在TLR 2（-/-）-心脏中，BoxA和HMGB 1均不影响梗死面积。未检测到TLR 4和TLR 9表达的差异，而TLR 2（-/-）-小鼠显示TLR 4和HMGB 1表达增加。在携带TLR 2多态性（Arg 753 Gln）的患者中，CABG手术后TLR 2（-/-）-小鼠的血浆HMGB 1水平增加。我们在这里提供的证据表明，TLR 2信号的缺乏消除了HMGB 1阻断的心肌梗死保护作用。
Genetic or pharmacological ablation of toll-like receptor 2 (TLR2) protects against myocardial ischemia/reperfusion injury (MI/R). However, the endogenous ligand responsible for TLR2 activation has not yet been detected. The objective of this study was to identify HMGB1 as an activator of TLR2 signalling during MI/R. C57BL/6 wild-type (WT) or TLR2(-/-)-mice were injected with vehicle, HMGB1, or HMGB1 BoxA one hour before myocardial ischemia (30 min) and reperfusion (24 hrs). Infarct size, cardiac troponin T, leukocyte infiltration, HMGB1 release, TLR4-, TLR9-, and RAGE-expression were quantified. HMGB1 plasma levels were measured in patients undergoing coronary artery bypass graft (CABG) surgery. HMGB1 antagonist BoxA reduced cardiomyocyte necrosis during MI/R in WT mice, accompanied by reduced leukocyte infiltration. Injection of HMGB1 did, however, not increase infarct size in WT animals. In TLR2(-/-)-hearts, neither BoxA nor HMGB1 affected infarct size. No differences in RAGE and TLR9 expression could be detected, while TLR2(-/-)-mice display increased TLR4 and HMGB1 expression. Plasma levels of HMGB1 were increased MI/R in TLR2(-/-)-mice after CABG surgery in patients carrying a TLR2 polymorphism (Arg753Gln). We here provide evidence that absence of TLR2 signalling abrogates infarct-sparing effects of HMGB1 blockade.