title: High-mobility group box 1 (HMGB1) impaired cardiac excitation-contraction coupling by enhancing the sarcoplasmic reticulum (SR) Ca(2+) leak through TLR4-ROS signaling in cardiomyocytes.
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 Ca(2+) 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 Ca(2+) sparks, reduced the sarcoplasmic reticulum (SR) Ca(2+) content, and decreased the amplitude of systolic Ca(2+) transient and myocyte contractility in dose-dependent manners in adult rat ventricular myocytes. Inhibiting high-frequent Ca(2+) sparks with tetracaine largely inhibited the alterations of SR load and Ca(2+) transient. Blocking Toll-like receptor 4 (TLR4) with TAK-242 or knockdown of TLR4 by RNA interference remarkably inhibited HMGB1 induced high-frequent Ca(2+) sparks and restored the SR Ca(2+) content. Concomitantly, the amplitude of systolic Ca(2+) 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 Ca(2+) handling and myocyte contractility. Taken together, our findings suggest that HMGB1 enhances Ca(2+) spark-mediated SR Ca(2+) leak through TLR4-ROS signaling pathway, which causes partial depletion of SR Ca(2+) content and hence decreases systolic Ca(2+) transient and myocyte contractility. Prevention of SR Ca(2+) leak may be an effective therapeutic strategy for the treatment of cardiac dysfunction related to HMGB1 overproduction.
authors.affiliation: Department of Pathophysiology, Key Laboratory for Shock and Microcirculation Research, Southern Medical University, Guangzhou, China.
authors.forename: Cuicui
authors.initials: C
authors.lastname: Zhang
authors.affiliation: Department of Pathophysiology, School of Medicine, Shenzhen University, Shenzhen, China.
authors.forename: Miaohua
authors.initials: M
authors.lastname: Mo
authors.affiliation: Department of Pathophysiology, Key Laboratory for Shock and Microcirculation Research, Southern Medical University, Guangzhou, China.
authors.forename: Wenwen
authors.initials: W
authors.lastname: Ding
authors.affiliation: Department of Pathophysiology, School of Medicine, Shenzhen University, Shenzhen, China.
authors.forename: Wenjuan
authors.initials: W
authors.lastname: Liu
authors.affiliation: Department of Endocrinology, The First Affiliated Hospital of Shenzhen University, Shenzhen, China.
authors.forename: Dewen
authors.initials: D
authors.lastname: Yan
authors.affiliation: Department of Pathophysiology, Key Laboratory for Shock and Microcirculation Research, Southern Medical University, Guangzhou, China.
authors.forename: Jianxin
authors.initials: J
authors.lastname: Deng
authors.affiliation: Department of Pathophysiology, School of Medicine, Shenzhen University, Shenzhen, China.
authors.forename: Xinping
authors.initials: X
authors.lastname: Luo
authors.affiliation: Department of Pathophysiology, School of Medicine, Shenzhen University, Shenzhen, China; Department of Pathophysiology, Key Laboratory for Shock and Microcirculation Research, Southern Medical University, Guangzhou, China. Electronic address: ljljz@yahoo.com.
authors.forename: Jie
authors.initials: J
authors.lastname: Liu
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D002118:Calcium / Q000378:metabolism*; D020013:Calcium Signaling; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000235:genetics / Q000378:metabolism; D056966:Excitation Contraction Coupling / Q000235:genetics*; D005260:Female; D005786:Gene Expression Regulation; D024243:HMGB1 Protein / Q000235:genetics / Q000378:metabolism*; D006352:Heart Ventricles / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008665:Metalloporphyrins / Q000494:pharmacology; D032383:Myocytes, Cardiac / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D061251:Primary Cell Culture; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D019837:Ryanodine Receptor Calcium Release Channel / Q000235:genetics / Q000378:metabolism; D012519:Sarcoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism*; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D013449:Sulfonamides / Q000494:pharmacology; D013748:Tetracaine / Q000494:pharmacology; D051197:Toll-Like Receptor 4 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*
chemical_list: D024243:HMGB1 Protein; C104200:Hbp1 protein, rat; D008665:Metalloporphyrins; D017382:Reactive Oxygen Species; D019837:Ryanodine Receptor Calcium Release Channel; D013449:Sulfonamides; C495347:Tlr4 protein, rat; D051197:Toll-Like Receptor 4; C507035:ethyl 6-(N-(2-chloro-4-fluorophenyl)sulfamoyl)cyclohex-1-ene-1-carboxylate; C097284:manganese(III)-tetrakis(4-benzoic acid)porphyrin; D013748:Tetracaine; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D002118:Calcium
keywords: Ca(2+) transient; HMGB1; Reactive oxygen species (ROS); SR Ca(2+) content; Sarcoplasmic reticulum (SR) Ca(2+) leak; Toll-like receptor (TLR) 4