Innate immunity mediates myocardial preconditioning through Toll-like receptor 2 and TIRAP-dependent signaling pathways
Innate immunity mediates myocardial preconditioning through Toll-like receptor 2 and TIRAP-dependent signaling pathways
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DOI：
10.1152/ajpheart.00306.2009
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发表时间：
2010-03-01
影响因子：
4.8
通讯作者：
Mann, Douglas L.
中科院分区：
文献类型：
--
作者：
Dong, Jian-Wen;Vallejo, Jesus G.;Mann, Douglas L.
[10] Dong J，巴列霍JG，Tzeng H，托马斯JA，Mann DL.天然免疫通过Toll样受体2和TIRAP依赖性信号通路介导心肌预适应Am J Physiol Heart Circ Physiol 298：H1079-H1087，2010.首次发表于2010年1月8日; doi：10.1152/ajpheart.00306.2009。最近的研究表明，Toll样受体2（TLR 2）和TLR 4信号转导参与了缺血再灌注（I/R）后肝脏和脑损伤的界定。为了确定TLR 2和TLR 4是否赋予心脏细胞保护作用，我们对野生型（WT）小鼠和TLR 2（TLR 2D）、TLR 4（TLR 4D）和含TIR结构域的衔接蛋白（TIRAP-D）缺陷小鼠的心脏进行缺血预处理（IPC）。Langendorff灌流心脏进行30分钟缺血和60分钟再灌注与IPC或没有。IPC导致WT小鼠心脏中左心室发展压力（%LVDP）恢复百分比显著增加（P < 0.05）（基线的54.4 +/- 2.7%），而TIRAP-D小鼠心脏中I/R损伤后%LVDP无显著增加（P > 0.05）（43.8 +/- 1.9%）。IPC还导致WT心脏I/R诱导的肌酸激酶释放和Evans蓝染料摄取显著降低（P < 0.05），但TIRAP-D心脏无此作用。有趣的是，IPC导致TLR 4缺陷型心脏（52.7 +/-3%）的%LVDP显著增加（P < 0.05），但TLR 2D心脏（39.3 +/-1.5%）未增加。用特异性TLR 2配体（Pam 3CSK）预处理保护WT心脏免受I/R诱导的左心室功能障碍。在TIRAP-D小鼠心脏中IPC诱导的心脏保护作用的丧失伴随着蛋白激酶C-ERK的易位减少和GSK-3 β的磷酸化减少。总之，这些数据表明IPC的心脏保护作用至少部分是通过TLR 2-TIRAP依赖性途径介导的，表明该途径的调节代表了减少I/R损伤的可行靶点。
Dong J, Vallejo JG, Tzeng H, Thomas JA, Mann DL. Innate immunity mediates myocardial preconditioning through Toll-like receptor 2 and TIRAP-dependent signaling pathways. Am J Physiol Heart Circ Physiol 298: H1079-H1087, 2010. First published January 8, 2010; doi:10.1152/ajpheart.00306.2009.-Recent studies have implicated Toll-like receptor 2 (TLR2) and TLR4 signaling in delimiting liver and brain injury following ischemia-reperfusion (I/R). To determine whether TLR2 and TLR4 conferred cytoprotection in the heart, we subjected hearts of wild-type (WT) mice and mice deficient in TLR2 (TLR2D), TLR4 (TLR4D), and TIR domain-containing adapter protein (TIRAP-D) to ischemic preconditioning (IPC). Langendorff-perfused hearts were subjected to 30 min ischemia and 60 min reperfusion with or without IPC. IPC resulted in a significant increase (P < 0.05) in the percent recovery of left ventricular developed pressure (%LVDP) in WT mouse hearts (54.4 +/- 2.7% of baseline), whereas there was no significant increase in %LVDP (P > 0.05) in TIRAP-D mouse hearts (43.8 +/- 1.9%) after I/R injury. IPC also resulted in a significant (P < 0.05) decrease in I/R-induced creatine kinase release and Evans blue dye uptake in WT but not TIRAP-D hearts. Interestingly, IPC resulted in a significant (P < 0.05) increase in %LVDP in TLR4-deficient hearts (52.7 +/- 3%) but not in TLR2D hearts (39.3 +/- 1.5%). Pretreatment with a specific TLR2 ligand (Pam3CSK) protected WT hearts against I/R-induced left ventricular dysfunction. The loss of IPC-induced cardioprotection in TIRAP-D mouse hearts was accompanied by a decreased translocation of protein kinase C-epsilon and decreased phosphorylation of GSK-3 beta. Taken together, these data suggest that the cardioprotective effect of IPC is mediated, at least in part, through a TLR2-TIRAP-dependent pathway, suggesting that the modulation of this pathway represents a viable target for reducing I/R injury.