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First published online March 28, 2008
Experimental Biology and Medicine doi: 10.3181/0706-RM-155
© 2008 by the Society for Experimental Biology and Medicine
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Mitochondrial Dysfunction and Redox Signaling in Atrial Tachyarrhythmia

Alicja Bukowska 1, Lorenz Schild 2, Gerburg Keilhoff 3, Daniel Hirte 2, Manfred Neumann 2, Andreas Gardemann 2, Klaus Hinrich Neumann 2, Christof Huth 2, Friedrich-Wilhelm Röhl 2, Andreas Goette 2, and Uwe Lendeckel 2*

1 University Hospital Magdenurg
2 University Hospital Magdeburg
3 University of Magdeburg

* To whom correspondence should be addressed. E-mail: uwe.lendeckel{at}med.ovgu.de.


  Abstract

Objective: Accumulating evidence links calcium-overload and oxidative stress to atrial remodeling during atrial fibrillation (AF). Furthermore, atrial remodeling appears to increase atrial thrombogeneiety, characterised by increased expression of adhesion molecules. The aim of this study was to assess mitochondrial dysfunction and oxidative stress-activated signal transduction (NF-{kappa} B, LOX-1, ICAM-1, and HO-1) in atrial tissue during AF. Methods: Ex vivo atrial tissue from patients with and without AF and, additionally, rapid pacing of organotypic human atrial tissue slices were used to study mitochondrial structure by electron microscopy and mitochondrial respiration. Furthermore, quantitative RT-PCR, immunoblot analyses, and gel-shift assays and ELISA were applied to measure nuclear amounts of NF-{kappa} B and target gene expression. Results: Using ex vivo atrial tissue samples from patients with AF we demonstrated oxidative stress and impaired mitochondrial structure and respiration, which was accompanied by nuclear accumulation of NF-{kappa} B and elevated expression levels of the adhesion molecule ICAM-1 and the oxidative stress-induced factors HO-1 and LOX-1. All these changes were reproduced by rapid pacing for 24 hours of human atrial tissue slices. Furthermore, the blockade of calcium inward current with verapamil effectively prevented both the mitochondrial changes and the activation of NF-{kappa} B signaling and target gene expression. The latter appeared to be diminshed by the antioxidants apocynin and resveratrol, an inhibitor of NF-{kappa} B, or the angiotensin II type 1 receptor antagonist, olmesartan. Conclusion: Calcium inward current via L-type calcium channels contributes to oxidative stress and increased expression of oxidative stress markers and adhesion molecules during cardiac tachyarrhythmia.

Key Words: arrhythmia, redox signaling, Ca-channel, LOX-1




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A. Bukowska, U. Lendeckel, A. Krohn, G. Keilhoff, S. t. Have, K. H. Neumann, and A. Goette
Atrial fibrillation down-regulates renal neutral endopeptidase expression and induces profibrotic pathways in the kidney
Europace, October 1, 2008; 10(10): 1212 - 1217.
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Copyright © 2008 by the Society for Experimental Biology and Medicine.