title: Ablation of junctin or triadin is associated with increased cardiac injury following ischaemia/reperfusion.
abstract: OBJECTIVE
  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 heart's responses to ischaemia/reperfusion (I/R) injury.
  
  
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Pharmacology and Cell Biophysics, University of Cincinnati College of Medicine, Cincinnati, OH 45267-0575, USA.
authors.forename: Wen-Feng
authors.initials: WF
authors.lastname: Cai
authors.forename: Tracy
authors.initials: T
authors.lastname: Pritchard
authors.forename: Stela
authors.initials: S
authors.lastname: Florea
authors.forename: Chi-Kueng
authors.initials: CK
authors.lastname: Lam
authors.forename: Peidong
authors.initials: P
authors.lastname: Han
authors.forename: Xiaoyang
authors.initials: X
authors.lastname: Zhou
authors.forename: Qunying
authors.initials: Q
authors.lastname: Yuan
authors.forename: Stephan E
authors.initials: SE
authors.lastname: Lehnart
authors.forename: Paul D
authors.initials: PD
authors.lastname: Allen
authors.forename: Evangelia G
authors.initials: EG
authors.lastname: Kranias
mesh_terms: D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D002118:Calcium / Q000378:metabolism*; D020013:Calcium Signaling; D002135:Calcium-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D002154:Calpain / Q000235:genetics / Q000378:metabolism*; D002155:Calsequestrin / Q000235:genetics / Q000378:metabolism; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D004151:Dipeptides / Q000494:pharmacology* / Q000627:therapeutic use; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D006899:Mixed Function Oxygenases / Q000235:genetics / Q000378:metabolism*; D009124:Muscle Proteins / Q000235:genetics / Q000378:metabolism*; D009200:Myocardial Contraction / Q000502:physiology; D009203:Myocardial Infarction / Q000188:drug therapy / Q000378:metabolism*; D015427:Reperfusion Injury / Q000150:complications / Q000378:metabolism*
chemical_list: D002135:Calcium-Binding Proteins; D002155:Calsequestrin; D002352:Carrier Proteins; D015853:Cysteine Proteinase Inhibitors; D004151:Dipeptides; D008565:Membrane Proteins; D009124:Muscle Proteins; C070048:triadin; C498841:Asph protein, mouse; D006899:Mixed Function Oxygenases; D002154:Calpain; D002118:Calcium; C058076:calpain inhibitor III