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lüll Ablation of junctin or triadin is associated with increased cardiac injury following ischaemia/reperfusion Cai WF; Pritchard T; Florea S; Lam CK; Han P; Zhou X; Yuan Q; Lehnart SE; Allen PD; Kranias EGCardiovasc Res 2012[May]; 94 (2): 333-41AIMS: 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. 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.|Animals[MESH]|Apoptosis[MESH]|Blotting, Western[MESH]|Calcium Signaling[MESH]|Calcium-Binding Proteins/genetics/*metabolism[MESH]|Calcium/*metabolism[MESH]|Calpain/genetics/*metabolism[MESH]|Calsequestrin/genetics/metabolism[MESH]|Carrier Proteins/genetics/*metabolism[MESH]|Cysteine Proteinase Inhibitors/pharmacology/therapeutic use[MESH]|Dipeptides/*pharmacology/therapeutic use[MESH]|Humans[MESH]|Membrane Proteins/genetics/*metabolism[MESH]|Mice[MESH]|Mixed Function Oxygenases/genetics/*metabolism[MESH]|Muscle Proteins/genetics/*metabolism[MESH]|Myocardial Contraction/physiology[MESH]|Myocardial Infarction/drug therapy/*metabolism[MESH]|Reperfusion Injury/complications/*metabolism[MESH] |