Activation of proteolysis by calpains and structural changes in human paroxysmal and persistent atrial fibrillation.
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.
Brundel
Bianca J J M
BJ
Department of Clinical Pharmacology, Groningen University Institute for Drug Exploration, Groningen, The Netherlands. b.j.j.m.brundel@med.rug.nl
Ausma
Jannie
J
van Gelder
Isabelle C
IC
Van der Want
Johan J L
JJ
van Gilst
Wiek H
WH
Crijns
Harry J G M
HJ
Henning
Robert H
RH
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
D011506:Proteins; D002154:Calpain