Biomedical Engineering Reference
In-Depth Information
Fig. 3
Oxidative stress in AF. Altered intracellular calcium (Ca
2+
) homeostasis and activation of
AT1R have been identii ed as factors contributing to oxidative stress in atrial myocardium. Local
activation of the renin angiotensin system (A S) leads to activation of the angiotensin receptor
(AT1R) via ligation of angiotensin II (AngII). h is leads to increased activation of the nicotinamide
adenine dinucleotide phosphate (NADPH) oxidase and consecutive overproduction of reactive
oxygen species (ROS). Angiotensin receptor blockers (ARB) and NADPH oxidase inhibitor
apocynin can decrease ROS production. Altered Ca
2+
handling leads to intracellular Ca
2+
overload
enhancing oxidative stress. h
is process can be mitigated by calcium receptor antagonists, like
verapamil.
Elevated ROS and Ca
2+
levels are major activators of transcription factor NF-
κB. Nuclear accumulation of NF-κB was observed in both
ex vivo
atrial tissue from
patients with AF and in atrial tissue slices rapidly paced
in vitro
. As concluded
from a supershit analysis we performed, the classical p50/p65 NF-κB components
are involved in this setting (Bukowska
et al.
2008). Typical target genes of NF-
κB are pro-inl ammatory cytokines such as interleukin-8 and tumor necrosis
factor alpha (TNF-α), but also the endothelial adhesion molecules vascular cell
adhesion molecule 1 (VCAM-1), intercellular adhesion molecule 1 (ICAM-1),
and the endothelial lectin-like oxidized low-density lipoprotein receptor receptor
(LOX-1). h e LOX-1 promoter contains binding sites for numerous transcription
factors, including NF-κB and AP-1. Recent studies demonstrated that AngII, by
activating NF-κB, induces LOX-1 promoter activation in endothelial cells. Our
studies coni rmed these i ndings and also showed that LOX-1 induction could be
prevented by the NADPH oxidase inhibitor apocynin and resveratrol, an inhibitor
of NF-κB (Bukowska
et al.
2008). Phosphorylation of IκB is a critical regulatory
step in the activation of NF-κB. Release from IκB unmasks the nuclear localization
signal of NF-κB and thus mediates its translocation into the cell nucleus. In our
