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κ阿片受体激动剂通过调控Toll样受体4/核因子-κB信号通路保护大鼠缺血再灌注心肌 被引量:5

κ-opioid receptor agonist U50,488H attenuates myocardial ischemia-reperfusion via modulating Toll-like receptor 4/nuclear factor-κB signaling in rat
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摘要 目的 研究选择性κ阿片受体(κ-opioid receptor,κ-OR)激动剂U50,488H对大鼠缺血再灌注心肌的保护作用,及其与Toll样受体4(TLR4)/核因子-κB(NF-κB)信号通路的关系.方法 成年健康雄性SD大鼠,体质量250 ~ 300 g,由第四军医大学动物实验中心提供.采用随机区组法将大鼠分为未阻断左前降支血流的对照组,心肌缺血再灌注组(I/R组),使用U50,488H的心肌缺血再灌注组(I/R+ U50组)以及加用κ-OR特异性阻断剂Nor-BNI和U50,488H的心肌缺血再灌注组(I/R+ U50+N组).使用丝线短暂阻断大鼠冠状动脉左前降支血流30 min,再灌注120 min,建立大鼠心肌缺血再灌注模型.在缺血前由静脉选择注射U50,488H和(或)κ-OR激动剂的阻断剂(Nor-BNI).对照组接受相同的手术过程,但未阻断左前降支血流.采用伊文思蓝和TTC染色检测大鼠心肌梗死面积.观察心律失常发生情况并计算心律失常评分.灌注结束后分别选取心肌梗死后的梗死区域、缺血区域、临近缺血区域的正常心肌区域(危险区域)检测TLR4、NF-κB、肿瘤坏死因-α(TNF-α)和髓过氧化物酶(MPO)的表达水平.结果 I/R+ U50组大鼠心肌梗死面积小于I/R组(P<0.01),而I/R+U50+N组则大于I/R+ U50组(P<0.01).I/R+ U50组大鼠室性心动过速和心室颤动的发生率均低于I/R组(P均<0.01),心律失常评分亦低于I/R组(2.9±0.7比4.4±0.9,P<0.05).而I/R+ U50+N组室性心动过速和心室颤动的发生率均高于I/R+U50组(P均<0.01),心律失常评分亦高于I/R+ U50组(4.5±0.8比2.9±0.7,P<0.01).I/R+ U50组大鼠心肌缺血区域和危险区域中的TLR4、NF-κB、TNF-α和MPO的表达水平均低于I/R组(P均<0.01),而I/R+ U50+N组则均高于I/R+ U50组(P均<0.01).结论 κ-OR激动剂U50,488H对大鼠缺血再灌注心肌具有保护作用,且该作用可能是通过TLR4/NF-κB信号通路实� Objective To observe the effects of κ-opioid receptor agonist U50,488H on myocardial ischemia and reperfusion injury and related mechanism.Methods Rats were randomly divided into sham operation,myocardial ischemia and reperfusion(I/R,30 min ischemia followed by 120 min reperfusion),and MI/R + U50,488H (1.5 mg/kg) and I/R + U50,488H + selective κ-opioid receptor antagonist Nor-BNI (2 mg/kg,n =8 each).The infarction size and the incidence of ventricular arrhythmias were observed.Real-time PCR and DAB staining were used to define the myocardium Toll-like receptor 4 (TLR4)expression.Myeloperoxidase level,TNF-α induction and the expression of NF-κB were also examined in rats.Results After I/R,the expressions of myocardial TLR4 and NF-κB increased significantly both in ischemia area and area at risk.Compared with I/R,κ-opioid receptor stimulation with U50,488H significantly attenuated the expressions of TLR4 and NF-κB and reduced myeloperoxidase (MPO) levels,myocardial TNF-α production,myocardial infarct sizes and the incidence of ventricular arrhythmias and arrhythmia score (2.9 ±0.7 vs.4.4 ± 0.9,P 〈 0.05),above effects of U50,488H were partly abolished by co-treatment with Nor-BNI.Conclusion These data provide evidence for the first time that κ-opioid receptor stimulation could attenuate myocardial L/R injury via downregulating TLR4/NF-κB signaling in rats.
出处 《中华心血管病杂志》 CAS CSCD 北大核心 2014年第10期866-872,共7页 Chinese Journal of Cardiology
关键词 心肌再灌注损伤 受体 阿片样 κ TOLL样受体4 NF-ΚB Myocardial reperfusion injury Receptors,opioid,kappa Toll-like receptor 4 NF-kappa B
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