title: Calpain I inhibition prevents atrial structural remodeling in a canine model with atrial fibrillation.
abstract: BACKGROUND
  Atrial fibrillation (AF) is accompanied by atrial structural remodeling. Calpain activity is induced during AF. To test a causal relationship between calpain activation and atrial structural changes, N-acetyl-Leu-Leu-Met (ALLM), a calpain inhibitor, was utilized in a canine AF model.
  
  
  METHODS
  Fifteen dogs were randomly divided into 3 groups: sham-operated group, control group and calpain inhibitor group; each with 5 dogs. Sustained AF was induced by rapid right atrium pacing at 600 beats per minute for 3 weeks. ALLM was administered at a dosage of 1.0 mg x kg(-1) x d(-1) in the calpain inhibitor group. Three weeks later, the proteolysis, protein expression of TnT and myosin, calpain I localization and expression and structural changes were examined in left atrial free walls, right atrial free walls and the interatrial septum respectively. Atrial size and contractile function were also measured by echocardiography.
  
  
  RESULTS
  Long-term rapid atrial pacing induced marked structural changes such as enlarged atrial volume, myolysis, degradation of TnT and myosin, accumulation of glycogen and changes in mitochondrial shape and size, which were paralleled by an increase in calpain activity. The positive correlation between calpain activity and the degree of myolysis (r(s) = 0.90 961, P < 0.0001) was demonstrated. In addition to structural abnormalities, pacing-induced atrial contractile dysfunction was observed in this study. The pacing-induced atrial structural alterations and loss of contractility were partially prevented by the calpain inhibitor ALLM.
  
  
  CONCLUSIONS
  Activation of calpain represents key features in the progression towards overt structural remodeling. Calpain inhibitor, ALLM, suppressed the increased calpain activity and reversed structural remodeling caused by sustained atrial fibrillation in the present model. Calpain inhibition may therefore provide a possibility for therapeutic intervention in AF.
authors.affiliation: Department of Cardiology, First Clinical Hospital of Harbin Medical University, Harbin, Heilongjiang 150001, China.
authors.forename: Hong-jie
authors.initials: HJ
authors.lastname: Xue
authors.forename: Wei-min
authors.initials: WM
authors.lastname: Li
authors.forename: Yue
authors.initials: Y
authors.lastname: Li
authors.forename: Yong-tai
authors.initials: YT
authors.lastname: Gong
authors.forename: Bao-feng
authors.initials: BF
authors.lastname: Yang
authors.forename: Cheng-luo
authors.initials: CL
authors.lastname: Jin
authors.forename: Li
authors.initials: L
authors.lastname: Sheng
authors.forename: Shan
authors.initials: S
authors.lastname: Chu
authors.forename: Li
authors.initials: L
authors.lastname: Zhang
authors.forename: Hong-bo
authors.initials: HB
authors.lastname: Shan
authors.forename: Jie
authors.initials: J
authors.lastname: Liu
mesh_terms: D000818:Animals; D001281:Atrial Fibrillation / Q000473:pathology*; D002154:Calpain / Q000037:antagonists & inhibitors*; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology*; D004195:Disease Models, Animal; D004285:Dogs; D006325:Heart Atria / Q000473:pathology* / Q000648:ultrastructure; D009218:Myosins / Q000032:analysis; D020107:Troponin T / Q000032:analysis
chemical_list: D015853:Cysteine Proteinase Inhibitors; D020107:Troponin T; D002154:Calpain; D009218:Myosins