title: Activation of proteolysis by calpains and structural changes in human paroxysmal and persistent atrial fibrillation.
abstract: OBJECTIVE
  Atrial fibrillation (AF) is accompanied by electrical, structural and ion-channel protein remodeling. We tested if proteolysis by calpain and proteasome is activated during AF, and studied the relation with the remodeling processes.
  
  
  METHODS
  Right atrial appendages were obtained from patients with paroxysmal (n=7) or persistent (n=10) lone AF and compared to controls (n=10) in sinus rhythm undergoing coronary artery bypass grafting (CABG). Proteolysis was measured using Suc-Leu-Leu-Val-Tyr-7-amino-4-methyl-coumarin. Protein expression of calpain I and II was assessed by Western-blot and calpain I localization by immunohistochemistry. Structural changes were quantified by counting atrial myocytes with contraction bands or hibernation.
  
  
  RESULTS
  Calpain activity was significantly increased in paroxysmal AF (2-fold, P<0.001) and persistent AF (3-fold, P<0.001), mainly due to calpain I activation. Increased calpain I protein expression was found in AF with Western blot and immunohistochemistry. Myocytes from all AF groups showed increased contraction bands, whereas hibernation was only found in persistent AF. Calpain activity correlated with L-type Ca(2+) channel and Kv1.5 protein amounts (r=-0.80, P<0.001 and r=-0.72, P<0.001, respectively), degree of structural changes (r=0.90, P<0.001), shortening of atrial effective refractory period (AERP) (basic cycle length 500 ms, r=-0.60, P<0.001) and AERP rate adaptation (r=-0.80, P<0.001).
  
  
  CONCLUSIONS
  Calpain activity is induced during AF and correlates with parameters of ion-channel protein, structural and electrical remodeling. The results suggest that calpain activation represents an important mechanism linking calcium overload to cellular adaptation mechanisms in human AF.
authors.affiliation: Department of Clinical Pharmacology, Groningen University Institute for Drug Exploration, Groningen, The Netherlands. b.j.j.m.brundel@med.rug.nl
authors.forename: Bianca J J M
authors.initials: BJ
authors.lastname: Brundel
authors.forename: Jannie
authors.initials: J
authors.lastname: Ausma
authors.forename: Isabelle C
authors.initials: IC
authors.lastname: van Gelder
authors.forename: Johan J L
authors.initials: JJ
authors.lastname: Van der Want
authors.forename: Wiek H
authors.initials: WH
authors.lastname: van Gilst
authors.forename: Harry J G M
authors.initials: HJ
authors.lastname: Crijns
authors.forename: Robert H
authors.initials: RH
authors.lastname: Henning
mesh_terms: D000328:Adult; D000704:Analysis of Variance; D020517:Atrial Appendage / Q000737:chemistry / Q000378:metabolism* / Q000473:pathology; D001281:Atrial Fibrillation / Q000378:metabolism* / Q000473:pathology; D015153:Blotting, Western / Q000379:methods; D002154:Calpain / Q000032:analysis / Q000378:metabolism*; D016022:Case-Control Studies; D002452:Cell Count; D006801:Humans; D007150:Immunohistochemistry / Q000379:methods; D008854:Microscopy, Electron; D008875:Middle Aged; D011506:Proteins / Q000378:metabolism
chemical_list: D011506:Proteins; D002154:Calpain