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 Citations (Scopus)

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

Fingerprint

Reperfusion Injury
Reperfusion
Ischemia
Endoplasmic Reticulum Stress
Calpain
Transcription Factor CHOP
Caspase 12
Calsequestrin
Apoptosis
Ryanodine Receptor Calcium Release Channel
Troponin I
Sarcoplasmic Reticulum
triadin
Muscle Cells
Carrier Proteins
Proteins
Peptide Hydrolases
Up-Regulation
Phenotype

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., ... 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

Ablation of junctin or triadin is associated with increased cardiac injury following ischaemia/reperfusion. / Cai, Wen Feng; Pritchard, Tracy; Florea, Stela; Lam, Chi Kueng; Han, Peidong; Zhou, Xiaoyang; Yuan, Qunying; Lehnart, Stephan E.; Allen, Paul D.; Kranias, Evangelia G.

In: Cardiovascular Research, Vol. 94, No. 2, 01.05.2012, p. 333-341.

Research output: Contribution to journalArticle

Cai, WF, Pritchard, T, Florea, S, Lam, CK, Han, P, Zhou, X, Yuan, Q, Lehnart, SE, Allen, PD & Kranias, EG 2012, 'Ablation of junctin or triadin is associated with increased cardiac injury following ischaemia/reperfusion', Cardiovascular Research, vol. 94, no. 2, pp. 333-341. https://doi.org/10.1093/cvr/cvs119
Cai, Wen Feng ; Pritchard, Tracy ; Florea, Stela ; Lam, Chi Kueng ; Han, Peidong ; Zhou, Xiaoyang ; Yuan, Qunying ; Lehnart, Stephan E. ; Allen, Paul D. ; Kranias, Evangelia G. / Ablation of junctin or triadin is associated with increased cardiac injury following ischaemia/reperfusion. In: Cardiovascular Research. 2012 ; Vol. 94, No. 2. pp. 333-341.
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AU - Cai, Wen Feng

AU - Pritchard, Tracy

AU - Florea, Stela

AU - Lam, Chi Kueng

AU - Han, Peidong

AU - Zhou, Xiaoyang

AU - Yuan, Qunying

AU - Lehnart, Stephan E.

AU - Allen, Paul D.

AU - Kranias, Evangelia G.

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N2 - 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.

AB - 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.

KW - Calpain

KW - ER stress

KW - Ischaemia/reperfusion

KW - Junctin

KW - Triadin

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