Department of Physiology, National Key Discipline of Cell Biology, Fourth Military Medical University, Xi'an, 710032 Shaanxi Province, PR China.
Cytokine. 2013 Mar;61(3):842-8. doi: 10.1016/j.cyto.2013.01.002. Epub 2013 Feb 10.
It is well documented that the Toll-like receptor 4 (TLR4)/NF-κB signaling mediates early inflammation during myocardial ischemia and reperfusion. Our previous study has demonstrated that κ-opioid receptor stimulation with U50,488H produces cardioprotective and anti-inflammatory effects. The aim of the present study was to investigate whether κ-opioid receptor stimulation could modulate the TLR4/NF-κB signaling and reduce neutrophil accumulation and TNF-α induction in an ischemia-reperfusion injured rat heart model. Rats were randomly exposed to sham operation, myocardial ischemia and reperfusion (MI/R), and MI/R+U50,488H in the absence or presence of Nor-BNI, a selective κ-opioid receptor antagonist. The results demonstrated that after MI/R, the expressions of myocardial TLR4 and NF-κB increased significantly both in ischemia area and risking area. Compared with MI/R, κ-opioid receptor stimulation with U50,488H significantly attenuated the expressions of TLR4 and NF-κB. At the mean time, it also reduced myeloperoxidase (MPO) levels, both serum and myocardial TNF-α production, myocardial infarct sizes (INF/AAR%) and myocardial apoptosis induced by MI/R, all the effects of U50,488H were abolished by Nor-BNI. These data provide evidence for the first time that κ-opioid receptor stimulation inhibits TLR4/NF-κB signaling in the rat heart subjected to MI/R.
有充分的文献记载表明，Toll 样受体 4（TLR4）/NF-κB 信号通路介导了心肌缺血再灌注过程中的早期炎症反应。我们之前的研究表明，κ-阿片受体激动剂 U50,488H 可产生心脏保护和抗炎作用。本研究旨在探讨κ-阿片受体激动剂是否可以调节 TLR4/NF-κB 信号通路，减少缺血再灌注损伤大鼠心脏模型中的中性粒细胞浸润和 TNF-α的诱导。大鼠随机接受假手术、心肌缺血再灌注（MI/R）、MI/R+U50,488H 处理，同时给予或不给予选择性 κ-阿片受体拮抗剂 Nor-BNI。结果表明，在 MI/R 后，缺血区和危险区心肌 TLR4 和 NF-κB 的表达均明显增加。与 MI/R 相比，U50,488H 刺激 κ-阿片受体可显著减轻 TLR4 和 NF-κB 的表达。同时，还降低了髓过氧化物酶（MPO）水平、血清和心肌 TNF-α的产生、MI/R 诱导的心肌梗死面积（INF/AAR%）和心肌细胞凋亡。Nor-BNI 可完全阻断 U50,488H 的所有作用。这些数据首次提供了证据表明，在 MI/R 大鼠心脏中，κ-阿片受体刺激抑制了 TLR4/NF-κB 信号通路。
