1. Ablation of junctin or triadin is associated with increased cardiac injury following ischaemia/reperfusion.
- Author
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Cai, Wen-Feng, Pritchard, Tracy, Florea, Stela, Lam, Chi-Kueng, Han, Peidong, Zhou, Xiaoyang, Yuan, Qunying, Lehnart, Stephan E., Allen, Paul D., and Kranias, Evangelia G.
- Subjects
HEART injuries ,HUMAN genes ,ISCHEMIA ,MYOCARDIAL reperfusion ,CALSEQUESTRIN ,CARRIER proteins ,SARCOPLASMIC reticulum ,REPERFUSION injury - Abstract
Aims Junctin and triadin are calsequestrin-binding proteins that regulate sarcoplasmic reticulum (SR) Ca2+ 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 heart's responses to ischaemia/reperfusion (I/R) injury. Methods and results 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 Ca2+ 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. Conclusion 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. [ABSTRACT FROM PUBLISHER]
- Published
- 2012
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