Review article
Oxidative stress in atrial fibrillation: An emerging role of NADPH oxidase

https://doi.org/10.1016/j.yjmcc.2013.04.019Get rights and content

Highlights

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    Oxidative stress has been implicated in the pathogenesis of AF.

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    Activation of NADPH oxidase (NOX), particularly isoforms 2 and 4, occurs in humans with AF and experimental models of AF.

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    NOX can be activated by upstream substrates of AF such as Ang II and atrial stretch.

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    Inhibition of NOX by ACEI/AT1RB or Statins may have beneficial effects in preventing post-operative AF.

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.

Section snippets

Introduction: Atrial fibrillation and oxidative stress

Cardiac arrhythmias refer to abnormal rate or rhythm of the heartbeat caused by perturbed electrophysiology of the myocardium. Among many types of clinically significant arrhythmias, atrial fibrillation (AF) is most common; affecting 2.7 to 6.1 million adults in 2010 in the United States [1], among which 14–16% die of ischemic stroke [1]. AF incidence increases with aging. In particular, the percentage of stroke associated with AF rises steeply from 1.5% at age 50–59 years to 23.5% at age 80–89 

NOX in the heart: NOX2 vs. NOX4

The NAD(P)H oxidases (NOXs) are a family of multi-subunit enzymatic complexes. NOX isoforms [NOX1–5 or dual oxidase 1–2 (Duox)] recruit separate regulatory subunits for enzymatic assembly and activation [33]. NOX1–4 require p22phox (“phox” stands for phagocyte oxidase) as the membrane binding partner for their activation. NOX1 is composed of p47phox and/or its homologue NOXO1, as well as NOXA1, p40phox, and Rac1. Similarly, NOX2 (gp91phox in leukocytes) requires p47phox, p67phox, p40phox, and

Role of NOX in AF

AF is associated with oxidative stress [60]. Table 1 summarizes systemic or myocardial oxidative stress observed in AF patients and experimental models. It should be noted that each study used different atrial tissues and/or at different stages of AF.

Role of ROS in mediating initiation of AF and thromboembolic complication: AF begets AF as NOX begets NOX

Despite the clear link between oxidative stress and AF, it remains unclear whether oxidative stress is a causal factor for AF, or, conversely, a consequence of AF.

Pulmonary veins (PV) have been recognized as the sites of origin of premature atrial extrasystoles that can initiate AF [69], [70]. Indeed, ablation therapy has been known to be effective in patients with paroxysmal AF by disconnecting electrical conduction from PV to LA. Of note, H2O2 has been demonstrated to trigger irregular

Interventions potentially targeting NOX in AF

The spectrum of antioxidant treatments in AF has been reviewed extensively [29]. As summarized in Table 2, treatment with vitamin C, vitamin C in combination with vitamin E or N-acetylcysteine (NAC), each of which has antioxidant actions, reduced post-operative AF. However, evidences as to whether general antioxidant treatments are effective to prevent AF are conflicting. Therefore, approaches targeting more specific ROS-generating pathways have received increasing attention.

Conclusions

AF has become more and more prevalent and now a major public health problem [98]. Although AF is clearly associated with aging, and cardiovascular conditions such as hypertension, mitral valve disease and heart failure, the underlying molecular mechanisms have remained elusive [98]. Recent developments suggest that AF is promoted by atrial structural and electrical remodeling, and that AF itself further augments these responses to perpetuate AF [99], [100]. The known risk factors for AF have

Disclosure statement

The authors have nothing to disclose.

Acknowledgment

The authors work has been supported by the National Heart, Lung and Blood Institute (NHLBI) Grants HL077440 (HC), HL081571 (HC), HL088975 (HC), HL101228 (PPP, JNW, HC), and HL108701 (HC, DGH), an American Heart Association Established Investigator Award 12EIA8990025 (HC), and a National Natural Science Foundation of China (NSFC) Award 31028005 (HC, DPL).

References (119)

  • P. Korantzopoulos et al.

    Oral vitamin C administration reduces early recurrence rates after electrical cardioversion of persistent atrial fibrillation and attenuates associated inflammation

    Int J Cardiol

    (2005)
  • H. Cai et al.

    The vascular NAD(P)H oxidases as therapeutic targets in cardiovascular diseases

    Trends Pharmacol Sci

    (2003)
  • D. Jagnandan et al.

    Novel mechanism of activation of NADPH oxidase 5. Calcium sensitization via phosphorylation

    J Biol Chem

    (2007)
  • J.D. Lambeth et al.

    Regulation of Nox and Duox enzymatic activity and expression

    Free Radic Biol Med

    (2007)
  • Y. Maejima et al.

    Regulation of myocardial growth and death by NADPH oxidase

    J Mol Cell Cardiol

    (2011)
  • K.D. Martyn et al.

    Functional analysis of Nox4 reveals unique characteristics compared to other NADPH oxidases

    Cell Signal

    (2006)
  • B. Burstein et al.

    Atrial fibrosis: mechanisms and clinical relevance in atrial fibrillation

    J Am Coll Cardiol

    (2008)
  • O. Adam et al.

    Role of Rac1 GTPase activation in atrial fibrillation

    J Am Coll Cardiol

    (2007)
  • C. Antoniades et al.

    Myocardial redox state predicts in-hospital clinical outcome after cardiac surgery effects of short-term pre-operative statin treatment

    J Am Coll Cardiol

    (2012)
  • T. Kawahara et al.

    Point mutations in the proline-rich region of p22phox are dominant inhibitors of Nox1- and Nox2-dependent reactive oxygen generation

    J Biol Chem

    (2005)
  • L. Gao et al.

    Mechanistic insights into folic acid-dependent vascular protection: dihydrofolate reductase (DHFR)-mediated reduction in oxidant stress in endothelial cells and angiotensin II-infused mice: a novel HPLC-based fluorescent assay for DHFR activity

    J Mol Cell Cardiol

    (2009)
  • A. Boldt et al.

    Expression of angiotensin II receptors in human left and right atrial tissue in atrial fibrillation with and without underlying mitral valve disease

    J Am Coll Cardiol

    (2003)
  • H. Verdejo et al.

    Systemic vascular cell adhesion molecule-1 predicts the occurrence of post-operative atrial fibrillation

    Int J Cardiol

    (2011)
  • M.P. Schneider et al.

    Prevention of atrial fibrillation by renin–angiotensin system inhibition a meta-analysis

    J Am Coll Cardiol

    (2010)
  • Y. Li et al.

    Probucol attenuates atrial structural remodeling in prolonged pacing-induced atrial fibrillation in dogs

    Biochem Biophys Res Commun

    (2009)
  • G. Casaclang-Verzosa et al.

    Structural and functional remodeling of the left atrium: clinical and therapeutic implications for atrial fibrillation

    J Am Coll Cardiol

    (2008)
  • V.L. Roger et al.

    Heart disease and stroke statistics—2012 update: a report from the American Heart Association

    Circulation

    (2012)
  • P.A. Wolf et al.

    Atrial fibrillation as an independent risk factor for stroke: the Framingham Study

    Stroke

    (1991)
  • E. Anter et al.

    Atrial fibrillation and heart failure: treatment considerations for a dual epidemic

    Circulation

    (2009)
  • E.J. Benjamin et al.

    Independent risk factors for atrial fibrillation in a population-based cohort. The Framingham Heart Study

    JAMA

    (1994)
  • J. Coromilas

    Obesity and atrial fibrillation: is one epidemic feeding the other?

    JAMA

    (2004)
  • A. Bielecka-Dabrowa et al.

    The mechanisms of atrial fibrillation in hyperthyroidism

    Thyroid Res

    (2009)
  • M.C. Sanguinetti et al.

    Antiarrhythmic drug target choices and screening

    Circ Res

    (2003)
  • M.M. Elahi et al.

    Tracing the origins of postoperative atrial fibrillation: the concept of oxidative stress-mediated myocardial injury phenomenon

    Eur J Cardiovasc Prev Rehabil

    (2008)
  • Y.M. Kim et al.

    A myocardial Nox2 containing NAD(P)H oxidase contributes to oxidative stress in human atrial fibrillation

    Circ Res

    (2005)
  • J. Zhang et al.

    NOX4-dependent hydrogen peroxide overproduction in human atrial fibrillation and HL-1 atrial cells: relationship to hypertension

    Front Physiol

    (2012)
  • H. Cai et al.

    Downregulation of endocardial nitric oxide synthase expression and nitric oxide production in atrial fibrillation: potential mechanisms for atrial thrombosis and stroke

    Circulation

    (2002)
  • R.B. Neuman et al.

    Oxidative stress markers are associated with persistent atrial fibrillation

    Clin Chem

    (2007)
  • E. Babusikova et al.

    Oxidative modification of rat cardiac mitochondrial membranes and myofibrils by hydroxyl radicals

    Gen Physiol Biophys

    (2004)
  • M.J. Mihm et al.

    Impaired myofibrillar energetics and oxidative injury during human atrial fibrillation

    Circulation

    (2001)
  • G.R. Li et al.

    Properties of human atrial ICa at physiological temperatures and relevance to action potential

    Am J Physiol

    (1997)
  • E.G. Daoud et al.

    Effect of verapamil and procainamide on atrial fibrillation-induced electrical remodeling in humans

    Circulation

    (1997)
  • A. Bukowska et al.

    Mitochondrial dysfunction and redox signaling in atrial tachyarrhythmia

    Exp Biol Med (Maywood)

    (2008)
  • C.A. Carnes et al.

    Ascorbate attenuates atrial pacing-induced peroxynitrite formation and electrical remodeling and decreases the incidence of postoperative atrial fibrillation

    Circ Res

    (2001)
  • M. Ozaydin et al.

    N-acetylcysteine for the prevention of postoperative atrial fibrillation: a prospective, randomized, placebo-controlled pilot study

    Eur Heart J

    (2008)
  • H. Cai

    Hydrogen peroxide regulation of endothelial function: origins, mechanisms, and consequences

    Cardiovasc Res

    (2005)
  • G.R. Drummond et al.

    Combating oxidative stress in vascular disease: NADPH oxidases as therapeutic targets

    Nat Rev Drug Discov

    (2011)
  • A.N. Lyle et al.

    Poldip2, a novel regulator of Nox4 and cytoskeletal integrity in vascular smooth muscle cells

    Circ Res

    (2009)
  • B. Lassegue et al.

    NADPH oxidases: functions and pathologies in the vasculature

    Arterioscler Thromb Vasc Biol

    (2010)
  • B. Lassegue et al.

    Biochemistry, physiology, and pathophysiology of NADPH oxidases in the cardiovascular system

    Circ Res

    (2012)

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