Ablation of junctin or triadin is associated with increased cardiac injury following ischaemia/reperfusion
Ablation of junctin or triadin is associated with increased cardiac injury following ischaemia/reperfusion
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DOI：
10.1093/cvr/cvs119
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发表时间：
2012-05-01
影响因子：
10.8
通讯作者：
Kranias, Evangelia G.
中科院分区：
文献类型：
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作者：
Cai, Wen-Feng;Pritchard, Tracy;Kranias, Evangelia G.
连接蛋白和triadin是钙固蛋白结合蛋白，通过与ryanodine受体相互作用调节肌浆网（SR） ca2的释放。在人类衰竭的心脏中，这些蛋白质的水平明显下调。然而，这种减少的意义目前尚不清楚。在这里，我们研究了这些辅助蛋白在心脏缺血/再灌注（I/R）损伤反应中的功能作用。对分离的小鼠心脏进行全局I/R，并对野生型（WT）、连接蛋白敲除（JKO）和三联体蛋白敲除（TKO）心脏的收缩参数进行评估。JKO和TKO均与i /R后收缩恢复明显下降有关。然而，消融triadin导致最严重的i /R后表型。TKO心脏的额外收缩损伤与线粒体死亡途径无关，但归因于内质网（ER）应激介导的细胞凋亡。x- box结合蛋白-1的激活和C/ ebp同源蛋白（CHOP）的转录上调提供了caspase-12依赖性肌细胞凋亡的分子机制。此外，再灌注时胞浆钙-2的升高与钙蛋白酶的激活和肌钙蛋白I的分解有关。因此，使用钙蛋白酶抑制剂MDL-28170治疗可显著改善完整心脏i /R后收缩恢复损伤。这些发现表明，连接蛋白或三联蛋白的缺乏会损害缺血后心脏的收缩恢复，这似乎主要归因于内质网应激增加和钙蛋白酶的激活。
Junctin and triadin are calsequestrin-binding proteins that regulate sarcoplasmic reticulum (SR) Ca-2 release by interacting with the ryanodine receptor. The levels of these proteins are significantly down-regulated in failing human hearts. However, the significance of such decreases is currently unknown. Here, we addressed the functional role of these accessory proteins in the hearts responses to ischaemia/reperfusion (I/R) injury.Isolated mouse hearts were subjected to global I/R, and contractile parameters were assessed in wild-type (WT), junctin-knockout (JKO), and triadin-knockout (TKO) hearts. Both JKO and TKO were associated with significantly depressed post-I/R contractile recovery. However, ablation of triadin resulted in the most severe post-I/R phenotype. The additional contractile impairment of TKO hearts was not related to a mitochondrial death pathway, but attributed to endoplasmic reticulum (ER) stress-mediated apoptosis. Activation of the X-box-binding protein-1 and transcriptional up-regulation of C/EBP-homologous protein (CHOP) provided a molecular mechanism of caspase-12-dependent apoptosis in myocytes. In addition, elevation of cytosolic Ca-2 during reperfusion was associated with the activation of calpain proteases and troponin I breakdown. Accordingly, treatment with the calpain inhibitor MDL-28170 significantly ameliorated post-I/R impairment of contractile recovery in intact hearts.These findings indicate that deficiency of either junctin or triadin impairs the contractile recovery in post-ischaemic hearts, which appears to be primarily attributed to increased ER stress and activation of calpain.