Sepsis is associated with cardiac dysfunction, which is at least in part due to cardiomyocyte apoptosis. However, the underlying mechanisms are far from being understood. Using the colon ascendens stent peritonitis mouse model of sepsis (CASP), we examined the subcellular mechanisms that mediate sepsis‐induced apoptosis. Wild‐type (WT) CASP mice hearts showed an increase in apoptosis respect to WT‐Sham. CASP transgenic mice expressing a CaMKII inhibitory peptide (AC3‐I) were protected against sepsis‐induced apoptosis. Dantrolene, used to reduce ryanodine receptor (RyR) diastolic sarcoplasmic reticulum (SR) Ca²⁺ release, prevented apoptosis in WT‐CASP. To examine whether CaMKII‐dependent RyR2 phosphorylation mediates diastolic Ca²⁺ release and apoptosis in sepsis, we evaluated apoptosis in mutant mice hearts that have the CaMKII phosphorylation site of RyR2 (Serine 2814) mutated to Alanine (S2814A). S2814A CASP mice did not show increased apoptosis. Consistent with RyR2 phosphorylation‐dependent enhancement in diastolic SR Ca²⁺ release leading to mitochondrial Ca²⁺ overload, mitochondrial Ca²⁺ retention capacity was reduced in mitochondria isolated from WT‐CASP compared to Sham and this reduction was absent in mitochondria from CASP S2814A or dantrolene‐treated mice. We conclude that in sepsis, CaMKII‐dependent RyR2 phosphorylation results in diastolic Ca²⁺ release from SR which leads to mitochondrial Ca²⁺ overload and apoptosis.

中文翻译：

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CaMKII依赖性兰尼碱受体磷酸化介导脓毒症诱导的心肌细胞凋亡


脓毒症与心脏功能障碍有关，这至少部分是由于心肌细胞凋亡造成的。然而，其根本机制还远未被了解。使用脓毒症结肠上升支架腹膜炎小鼠模型（CASP），我们检查了介导脓毒症诱导细胞凋亡的亚细胞机制。与 WT-Sham 相比，野生型 (WT) CASP 小鼠心脏的细胞凋亡有所增加。表达 CaMKII 抑制肽 (AC3-I) 的 CASP 转基因小鼠可免受脓毒症诱导的细胞凋亡。 Dantrolene 用于减少兰尼碱受体 (RyR) 舒张肌浆网 (SR) Ca ²⁺释放，可防止 WT-CASP 细胞凋亡。为了检查 CaMKII 依赖性 RyR2 磷酸化是否介导败血症中的舒张期 Ca ²⁺释放和细胞凋亡，我们评估了 RyR2 的 CaMKII 磷酸化位点（丝氨酸 2814）突变为丙氨酸（S2814A）的突变小鼠心脏的细胞凋亡。 S2814A CASP 小鼠没有表现出细胞凋亡增加。与 RyR2 磷酸化依赖性舒张期 SR Ca ²⁺释放增强导致线粒体 Ca ²⁺过载一致，与 Sham 相比，从 WT-CASP 分离的线粒体中线粒体 Ca ²⁺保留能力降低，而来自 CASP S2814A 的线粒体中不存在这种降低。或丹曲林治疗的小鼠。我们得出的结论是，在脓毒症中，CaMKII 依赖性 RyR2 磷酸化导致舒张期 Ca ²⁺从 SR 中释放，从而导致线粒体 Ca ²⁺过载和细胞凋亡。