Ablation of junctin or triadin is associated with increased cardiac injury following ischaemia/reperfusion

Wen Feng Cai, Tracy Pritchard, Stela Florea, Chi Kueng Lam, Peidong Han, Xiaoyang Zhou, Qunying Yuan, Stephan E. Lehnart, Paul D. Allen, Evangelia G. Kranias

Research output: Contribution to journalArticle

12 Scopus citations

Abstract

Aims 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. 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 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. 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.

Original languageEnglish (US)
Pages (from-to)333-341
Number of pages9
JournalCardiovascular Research
Volume94
Issue number2
DOIs
StatePublished - May 1 2012
Externally publishedYes

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Keywords

  • Calpain
  • ER stress
  • Ischaemia/reperfusion
  • Junctin
  • Triadin

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)
  • Physiology

Cite this

Cai, W. F., Pritchard, T., Florea, S., Lam, C. K., Han, P., Zhou, X., Yuan, Q., Lehnart, S. E., Allen, P. D., & Kranias, E. G. (2012). Ablation of junctin or triadin is associated with increased cardiac injury following ischaemia/reperfusion. Cardiovascular Research, 94(2), 333-341. https://doi.org/10.1093/cvr/cvs119