Oxidative stress in atrial fibrillation: an emerging role of NADPH oxidase

Abstract

Atrial fibrillation (AF) is the most common cardiac arrhythmia. Patients with AF have up to seven-fold higher risk of suffering from ischemic stroke. Better understanding of etiologies of AF and its thromboembolic complications are required for improved patient care, as current anti-arrhythmic therapies have limited efficacy and off target effects. Accumulating evidence has implicated a potential role of oxidative stress in the pathogenesis of AF. Excessive production of reactive oxygen species (ROS) is likely involved in the structural and electrical remodeling of the heart, contributing to fibrosis and thrombosis. In particular, NADPH oxidase (NOX) has emerged as a potential enzymatic source for ROS production in AF based on growing evidence from clinical and animal studies. Indeed, NOX can be activated by known upstream triggers of AF such as angiotensin II and atrial stretch. In addition, treatments such as statins, antioxidants, ACEI or AT1RB have been shown to prevent post-operative AF; among which ACEI/AT1RB and statins can attenuate NOX activity. On the other hand, detailed molecular mechanisms by which specific NOX isoform(s) are involved in the pathogenesis of AF and the extent to which activation of NOX plays a causal role in AF development remains to be determined. The current review discusses causes and consequences of oxidative stress in AF with a special focus on the emerging role of NOX pathways.

Keywords: Atrial fibrillation; NADPH oxidase; NOX2; NOX4; Oxidative stress; Structural and electrical remodeling.

Figure 1

Role of NADPH oxidase (NOX)-derived oxidative stress in atrial fibrillation (AF). Production of superoxide and H₂O₂ from activated NADPH oxidasae (NOX) isoforms 2 and 4 (NOX2, NOX4 respectively) leads to activation of downstream reactive oxygen species (ROS)-generating systems including mitochondrion and uncoupled eNOS, resulting in sustained oxidative stress which in turn stimulates myocyte apoptosis, atrial inflammation, fibrosis, and structural and electrical remodeling. Examples of key mediators downstream of increased ROS production include oxidized CaMKII (Ox-CaMKII) and activated nuclear factor kB (NF-kB). ox-CaMKII activates ryanodine receptor 2 (RyR2) hyperphospohrylation, which in turn causes secondary electrical remodeling and calcium overload-induced cardiac injury. NF-kB is a well known redox-sensitive transcriptional factor for inflammation and structural remodeling by activating TNF-alpha, iNOS, IL-1β, and MMPs. All these processes confer to NOX activators such as Ang II and atrial stretch, thus forming vicious cycle of NOX activation promoting AF, and AF promoting NOX activation. Endocardial nitric oxide deficiency due to oxidative stress and eNOS uncoupling may also contribute to thromboembolic complications of AF.