High-mobility group box 1 (HMGB1) impaired cardiac excitation-contraction coupling by enhancing the sarcoplasmic reticulum (SR) Ca2+ leak through TLR4-ROS signaling in cardiomyocytes
High-mobility group box 1 (HMGB1) impaired cardiac excitation-contraction coupling by enhancing the sarcoplasmic reticulum (SR) Ca2+ leak through TLR4-ROS signaling in cardiomyocytes
复制标题
高迁移率族盒1 (HMGB1) 通过心肌细胞中的TLR4-ROS 信号传导增强肌浆网(SR) Ca(2 ) 渗漏，从而损害心脏兴奋-收缩耦合。
DOI：
10.1016/j.yjmcc.2014.06.003
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发表时间：
2014-09-01
影响因子：
5
通讯作者：
Liu, Jie
中科院分区：
文献类型：
--
作者：
Zhang, Cuicui;Mo, Miaohua;Liu, Jie
高迁移率族蛋白1（HMGB 1）是一种促炎介质，在许多疾病的心功能不全的发病机制中起重要作用。本研究通过观察HMGB 1对心肌细胞Ca 2+处理和细胞收缩力的影响，探讨HMGB 1诱导心功能不全的机制。我们的研究结果表明，HMGB 1增加钙火花的频率，减少肌浆网（SR）的Ca 2+含量，并降低收缩期Ca 2+瞬变和心肌细胞收缩力的幅度在成年大鼠心室肌细胞中呈剂量依赖性的方式。用丁卡因抑制高频钙火花可显著抑制SR负荷和钙瞬变的改变。用TAK-242阻断Toll样受体4（TLR 4）或RNA干扰技术敲低TLR 4均能显著抑制HMGB 1诱导的高频钙火花，恢复SR钙含量，同时收缩期钙瞬变幅度和肌细胞收缩力显著增加。此外，HMGB 1增加细胞内活性氧（ROS）的水平，从而增强氧化应激和Ryanodine受体2（RyR 2）中CaMKII激活的磷酸化（pSer 2814）。TAK-242预处理显著降低了细胞内ROS水平以及RyR 2的氧化应激和过度磷酸化，与抗氧化剂MnTBAP的作用相似。同样，MnTBAP使HMGB 1受损的Ca 2+处理和肌细胞收缩性正常化。综上所述，我们的研究结果表明，HMGB 1通过TLR 4-ROS信号通路增强Ca 2+火花介导的SR Ca 2+泄漏，导致SR Ca 2+含量部分耗尽，从而降低收缩期Ca 2+瞬时和心肌细胞收缩力。预防SR Ca 2+渗漏可能是治疗HMGB 1过度产生相关心功能不全的有效治疗策略。(C)2014爱思唯尔有限公司版权所有。
High-mobility group box 1 (HMGB1) is a proinflammatory mediator playing an important role in the pathogenesis of cardiac dysfunction in many diseases. In this study, we explored the effects of HMGB1 on Ca2+ handling and cellular contractility in cardiomyocytes to seek for the mechanisms underlying HMGB1-induced cardiac dysfunction. Our results show that HMGB1 increased the frequency of Ca2+ sparks, reduced the sarcoplasmic reticulum (SR) Ca2+ content, and decreased the amplitude of systolic Ca2+ transient and myocyte contractility in dose-dependent manners in adult rat ventricular myocytes. Inhibiting high-frequent Ca2+ sparks with tetracaine largely inhibited the alterations of SR load and Ca2+ transient. Blocking Toll-like receptor 4 (TLR4) with TAK-242 or knockdown of TLR4 by RNA interference remarkably inhibited HMGB1 induced high-frequent Ca2+ sparks and restored the SR Ca2+ content Concomitantly, the amplitude of systolic Ca2+ transient and myocyte contractility had significantly increased. Furthermore, HMGB1 increased the level of intracellular reactive oxygen species (ROS) and consequently enhanced oxidative stress and CaMKII-activated phosphorylation (pSer2814) in ryanodine receptor 2 (RyR2). TAK-242 pretreatment significantly decreased intracellular ROS levels and oxidative stress and hyperphosphorylation in RyR2, similar to the effects of antioxidant MnTBAP. Consistently, MnTBAP normalized HMGB1-impaired Ca2+ handling and myocyte contractility. Taken together, our findings suggest that HMGB1 enhances Ca2+ spark-mediated SR Ca2+ leak through TLR4-ROS signaling pathway, which causes partial depletion of SR Ca2+ content and hence decreases systolic Ca2+ transient and myocyte contractility. Prevention of SR Ca2+ leak may be an effective therapeutic strategy for the treatment of cardiac dysfunction related to HMGB1 overproduction. (C) 2014 Elsevier Ltd. All rights reserved.