Mitochondrial dysfunction and redox signaling in atrial tachyarrhythmia.
Accumulating evidence links calcium-overload and oxidative stress to atrial remodeling during atrial fibrillation (AF). Furthermore, atrial remodeling appears to increase atrial thrombogeneity, characterized by increased expression of adhesion molecules. The aim of this study was to assess mitochondrial dysfunction and oxidative stress-activated signal transduction (nuclear factor-kappaB [NF-kappa B], lectin-like oxidized low-density lipoprotein receptor [LOX-1], intercellular adhesion molecule-1 [ICAM-1], and hemeoxgenase-1 [HO-1]) in atrial tissue during AF. Ex vivo atrial tissue from patients with and without AF and, additionally, rapid pacing of human atrial tissue slices were used to study mitochondrial structure by electron microscopy and mitochondrial respiration. Furthermore, quantitative reverse transcription polymerase chain reaction (RT-PCR), immunoblot analyses, gel-shift assays, and enzyme-linked immunosorbent assay (ELISA) were applied to measure nuclear amounts of NF-kappa B target gene expression. 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 markers 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 also diminished by the antioxidants apocynin and resveratrol (an inhibitor of NF-kappa B), or the angiotensin II receptor type 1 antagonist, olmesartan. This study demonstrates that 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.
Bukowska
Alicja
A
University Hospital Magdeburg, Institute of Experimental Internal Medicine, Leipzigerstrasse 44, 39120 Magdeburg, Germany.
Schild
Lorenz
L
Keilhoff
Gerburg
G
Hirte
Daniel
D
Neumann
Manfred
M
Gardemann
Andreas
A
Neumann
Klaus Hinrich
KH
Röhl
Friedrich-Wilhelm
FW
Huth
Christof
C
Goette
Andreas
A
Lendeckel
Uwe
U
D000368:Aged; D016275:Atrial Function / Q000235:genetics; D019069:Cell Respiration; D005260:Female; D005355:Fibrosis / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D051547:Heme Oxygenase-1 / Q000235:genetics / Q000378:metabolism; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics; D008297:Male; D008854:Microscopy, Electron; D028361:Mitochondrial Diseases / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D050050:Protein Carbonylation; D051127:Scavenger Receptors, Class E / Q000235:genetics; D015398:Signal Transduction; D013610:Tachycardia / Q000235:genetics / Q000378:metabolism* / Q000473:pathology
D016328:NF-kappa B; C495137:OLR1 protein, human; D051127:Scavenger Receptors, Class E; D018799:Intercellular Adhesion Molecule-1; C496541:HMOX1 protein, human; D051547:Heme Oxygenase-1