© 2002 by European Society of Cardiology
Copyright © 2002, European Society of Cardiology
Activation of proteolysis by calpains and structural changes in human paroxysmal and persistent atrial fibrillation
aDepartment of Clinical Pharmacology, Groningen University Institute for Drug Exploration (GUIDE), Groningen, The Netherlands
bDepartment of Cardiology, Thoraxcenter University Hospital, University of Groningen, Groningen, The Netherlands
cDepartment of Cell Biology and Electron Microscopy, University of Groningen, Groningen, The Netherlands
dDepartment of Physiology, Cardiovascular Research Institute Maastricht, University of Maastricht, Maastricht, The Netherlands
eDepartment of Cardiology, Cardiovascular Research Institute Maastricht, University of Maastricht, Maastricht, The Netherlands
* Corresponding author. Department of Radiation and Stress Cell Biology, Deusinglaan 1, 9713 AV Groningen, The Netherlands. Tel.: +31-50-363-2911; fax: +31-50-363-2913 b.j.j.m.brundel{at}med.rug.nl
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 Ca2+ 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.
KEYWORDS Apoptosis; Arrhythmia (mechanisms); Calcium (cellular); Hibernation; Remodeling; Supraventr. arrhythmia
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