Mitochondrial Dysfunction and Redox Signaling in Atrial Tachyarrhythmia

Abstract

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.

Protective regulation of the ACE2/ACE gene expression by estrogen in human atrial tissue from elderly men

“…Results of our group demonstrated the involvement of LOX-1 in the oxidative state within the right atrium in patients with AF. 55 Importantly, increased ''oxidative stress'' contributes to a pro-inflammatory and prothrombotic state of the atrial endomyocardium during AF. Obviously, future experiments should elucidate the in vivo relevance of E2 on atrial protection mechanisms.…”

Atrial remodeling in atrial fibrillation and association between microRNA network and atrial fibrillation

“…mRNA and protein levels of the transcrip- tion factor nuclear factor -B (NF-B) were increased in an atrial tachypacing canine model. Two research groups identified an accumulation of NF-B in human atrial tissue slices subjected to rapid pacing for 24 h, as well as in AF patients [37]. We verified that enhancement of NF-B up-regulated miR-328 transcription, using a chromatin immunoprecipitation assay.…”

The estimation of oxidative stress markers and apoptosis in right atrium auricles cardiomyocytes of patients undergoing surgical heart revascularisation with the use of warm blood cardioplegia.

“…Abraham et al presented an electromechanical dysfunction of myocardial specimens after remote exogenous ischemia-reperfusion [25], Canty et al determined the activation of oxidative stress-responsive transcription factor in homogenized auricule tissue [27]. Atrial tissue was also used by Bukowska et al for in vitro pacing experiments [28]. Wang et al proved the cardioprotective effect of osteopontin against cardiac ischemia-reperfusion injury by measuring the SOD activity and MDA content in cells [29].…”