Compromised redox homeostasis, altered nitroso-redox balance, and therapeutic possibilities in atrial fibrillation

Abstract

Although the initiation, development, and maintenance of atrial fibrillation (AF) have been linked to alterations in myocyte redox state, the field lacks a complete understanding of the impact these changes may have on cellular signalling, atrial electrophysiology, and disease progression. Recent studies demonstrate spatiotemporal changes in reactive oxygen species production shortly after the induction of AF in animal models with an uncoupling of nitric oxide synthase activity ensuing in the presence of long-standing persistent AF, ultimately leading to a major shift in nitroso-redox balance. However, it remains unclear which radical or non-radical species are primarily involved in the underlying mechanisms of AF or which proteins are targeted for redox modification. In most instances, only free radical oxygen species have been assessed; yet evidence from the redox signalling field suggests that non-radical species are more likely to regulate cellular processes. A wider appreciation for the distinction of these species and how both species may be involved in the development and maintenance of AF could impact treatment strategies. In this review, we summarize how redox second-messenger systems are regulated and discuss the recent evidence for alterations in redox regulation in the atrial myocardium in the presence of AF, while identifying some critical missing links. We also examine studies looking at antioxidants for the prevention and treatment of AF and propose alternative redox targets that may serve as superior therapeutic options for the treatment of AF.

Keywords: Antioxidants; Arrhythmia; Heart; Hydrogen peroxide; Nitric oxide; Subcellular localization.

Figure 1

Regulation of redox second messenger systems. Production of $[{{\text{O}}_2}^{-}]$ by membrane-bound NADPH oxidase is rapidly dismutated to form the non-radical oxidant H₂O₂. The diffusion of H₂O₂ (shown in blue) is highly restricted in this microdomain due to the expression of Prx, which acts to rapidly reduce H₂O₂ to water. H₂O₂ may also undergo further reduction to OH· via Fenton reaction in the presence of reduced metals. Targeting of protein thiols by OH· leads to generation of a thiyl radical (SO⁻). In this schematic, the diffusion distance of OH· (in purple) is shown relative to the diffusion distance of H₂O₂, based on previous calculations, to demonstrate how target substrate oxidation would be restricted to intracellular targets with this radius. The local environment will also influence the type of thiol modification induced by the oxidant. In this example, H₂O₂ reaction with a cysteine thiolate promotes formation of sulphenic acid (SOH). Sulphenic acid can then further react to form a disulphide bond with another reactive cysteine thiolate in close proximity (Reaction 1). Alternatively, glutathione may also react with the sulphenic acid to form a mixed disulphide (S-glutathionylation; Reaction 2). Chronic ROS elevations in the face of compromised antioxidant defences may, instead, promote formation of irreversible modifications such as sulphinic acid (SO₂H) (Reaction 3) and sulphonic acid (SO₃H) (Reaction 4). The downstream consequence of such modifications can vary, including: gain or loss of function of the modified protein; further propagation of the signal via transnitrosylation or by oxidant-induced activation of signalling kinases or phosphatases; and regulation of gene transcription by redox-sensitive transcription factors.

Figure 2

Known and predicted changes in compartmentalized redox homeostasis in permanent AF. The primary sources of oxidant generation in permanent AF include ROS produced from uncoupled NOS (within the membrane and/or cytosolic compartment) and the mitochondrial electron transport chain. The $[{{\text{O}}_2}^{-}]$ produced from uncoupled NOS is dismutated to H₂O₂ by SOD1, whose expression is increased in permanent AF, most likely to compensate for the increased $[{{\text{O}}_2}^{-}]$ production. In addition to increased production of H₂O₂, elimination of H₂O₂ is compromised by loss of cytosolic Prx1. This further increases localized H₂O₂ concentration and likely the diffusion distance for H₂O₂. Consequently, these alterations in local redox homeostasis would promote oxidation of nearby thiols, which may include Prx2 to promote sustained H₂O₂ levels, leading to a number of various downstream effects. In addition, NO production is reduced in permanent AF owing to both NOS uncoupling and loss of nNOS. Both the increase in ROS and the reduction in RNS negatively shift the nitroso–redox balance in favour of protein oxidation, which is thought to contribute to the electrical changes associated with AF.