Journal of molecular and cellular cardiology
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J. Mol. Cell. Cardiol. · Sep 2014
CaMKII-dependent phosphorylation of cardiac ryanodine receptors regulates cell death in cardiac ischemia/reperfusion injury.
Ca(2+)-calmodulin kinase II (CaMKII) activation is deleterious in cardiac ischemia/reperfusion (I/R). Moreover, inhibition of CaMKII-dependent phosphorylations at the sarcoplasmic reticulum (SR) prevents CaMKII-induced I/R damage. However, the downstream targets of CaMKII at the SR level, responsible for this detrimental effect, remain unclear. ⋯ This effect cannot be attributed to PKA-dependent PLN phosphorylation and was not due to the enhanced L-type Ca(2+) current, present in these mice. Our results reveal a major role for the phosphorylation of S2814 site on RyR2 in CaMKII-dependent I/R cardiac damage. In contrast, they showed that CaMKII-dependent increase in PLN phosphorylation during reperfusion opposes rather than contributes to I/R damage.
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J. Mol. Cell. Cardiol. · Sep 2014
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.
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. ⋯ 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.