Redox regulation, NF-kappaB, and atrial fibrillation

Abstract

Atrial fibrillation (AF) is the most common clinically encountered abnormal heart beat. It is associated with an increased risk of stroke and symptoms of heart failure. Current therapies are directed toward controlling the rate of ventricular activation and preventing strokes through anticoagulation. Attempts at suppressing the arrhythmia are often ineffective, in part because the underlying pathogenesis is poorly understood. Recently, structural and electrical remodeling has been shown to occur during AF. These changes involve alterations in gene regulation and help perpetuate the arrhythmia. Some signals for remodeling are have been identified. Moreover, AF is associated with oxidative stress, and this redox imbalance may contribute to the altered gene regulation. One likely mediator of this change in transcriptional regulation is the redox sensitive transcription factor, nuclear factor-kappaB (NF-kappaB). Recently, NF-kappaB has been shown to downregulate transcription of the cardiac sodium channel in response to oxidative stress. NF-kappaB may contribute to the regulation of other ion channels, transcription factors, or splicing factors altered in AF and may represent a therapeutic target in AF management.

FIG. 1.

Atrial fibrillation (AF) results in structural remodeling and electrical remodeling that contribute to the perpetuation of the arrhythmia. AF is caused by circus electrical activity in the atria and manifest by continuous low voltage fluctuations on the surface electrocardiogram with irregular conduction to the ventricle initiating the larger QRS deflections. Structural remodeling is characterized by increased fibrosis, and electrical remodeling is characterized by a shortening of the action potential duration.

FIG. 2.

Ion channel transcriptional events underlie part of the action potential shortening associated with atrial fibrillation (AF). Representative action potentials in AF and control are shown. Some of the ion channels contributing to the various currents during the action potential are indicated. I_Na, I_to, I_Ca, I_kr, I_ks stand for the sodium, transient outward, calcium, rapid delayed rectifier potassium, and slow delayed rectifier potassium currents, respectively. The relative position of the ion channels indicates the timing of their major activity during the action potential. Gene names encoding these currents are indicated in the parentheses.

FIG. 3.

Summary of identified signaling pathways involved in AF that may lead to NF-κB activation in atrial fibrillation (AF).

FIG. 4.

Three mechanisms by which oxidative stress and NF-κB activation may lead contribute to atrial fibrillation (AF). NF-κB can have direct effects on ion channel promoter regions, may alter other transcription factor expression levels, or may influence mRNA splicing.

FIG. 5.

A proposed scheme of how NF-κB may be involved in the pathogenesis of atrial fibrillation (AF). AF is known to be associated with systemic and cardiac oxidative stress. Oxidative stress can activate NF-κB. NF-κB has been shown to downregulate cardiac Na⁺ channels and may have other proarrhythmic effects, perpetuating AF.