Article ID | Journal | Published Year | Pages | File Type |
---|---|---|---|---|
8474760 | Journal of Molecular and Cellular Cardiology | 2014 | 14 Pages |
Abstract
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 Ca2Â + 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 Ca2Â + sparks, reduced the sarcoplasmic reticulum (SR) Ca2Â + content, and decreased the amplitude of systolic Ca2Â + transient and myocyte contractility in dose-dependent manners in adult rat ventricular myocytes. Inhibiting high-frequent Ca2Â + sparks with tetracaine largely inhibited the alterations of SR load and Ca2Â + transient. Blocking Toll-like receptor 4 (TLR4) with TAK-242 or knockdown of TLR4 by RNA interference remarkably inhibited HMGB1 induced high-frequent Ca2Â + sparks and restored the SR Ca2Â + content. Concomitantly, the amplitude of systolic Ca2Â + 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 Ca2Â + handling and myocyte contractility. Taken together, our findings suggest that HMGB1 enhances Ca2Â + spark-mediated SR Ca2Â + leak through TLR4-ROS signaling pathway, which causes partial depletion of SR Ca2Â + content and hence decreases systolic Ca2Â + transient and myocyte contractility. Prevention of SR Ca2Â + leak may be an effective therapeutic strategy for the treatment of cardiac dysfunction related to HMGB1 overproduction.
Keywords
Ca2 + transientNRVMsCa2 +-induced Ca2 + releaseMBBFWHMCaMKIIFDHMRyRNa+–Ca2 + exchangerDCFDAHMGB1NCXTLR4Neonatal rat ventricular myocytesROSMyocardial infarctionExcitation–contraction couplinghigh-mobility group box 1Sarcoplasmic reticulumFull width at half-maximumMonobromobimaneadult rat ventricular myocytesheart failureaction potentialCICRReactive oxygen species (ROS)Reactive oxygen speciesToll-like receptor 4Ryanodine receptor
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Authors
Cuicui Zhang, Miaohua Mo, Wenwen Ding, Wenjuan Liu, Dewen Yan, Jianxin Deng, Xinping Luo, Jie Liu,