期刊
JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY
卷 74, 期 -, 页码 260-273出版社
ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD
DOI: 10.1016/j.yjmcc.2014.06.003
关键词
HMGB1; Sarcoplasmic reticulum (SR) Ca2+ leak; SR Ca2+ content; Ca2+ transient; Toll-like receptor (TLR) 4; Reactive oxygen species (ROS)
资金
- National Natural Science Foundation of China [31171096, 31371159, 81200122]
- Basic Research Foundation of Shenzhen [JC201005250059A, JCYJ20120613115535998, JCYJ20130326112207234]
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.
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