Atrial fibrillation increases production of superoxide by the left atrium and left atrial appendage

Role of the NADPH and xanthine oxidases

Samuel C. Dudley, Nyssa E. Hoch, Louise A. McCann, Clegg Honeycutt, Laura Diamandopoulos, Tohru Fukai, David G. Harrison, Sergey I. Dikalov, Jonathan Langberg

Research output: Contribution to journalArticle

256 Citations (Scopus)

Abstract

Background - Atrial fibrillation (AF) is associated with an increased risk of stroke due almost exclusively to emboli from left atrial appendage (LAA) thrombi. Recently, we reported that AF was associated with endocardial dysfunction, limited to the left atrium (LA) and LAA and manifest as reduced nitric oxide (NO) production and increased expression of plasminogen activator inhibitor-1. We hypothesized that reduced LAA NO levels observed in AF may be associated with increased superoxide (O2 .-) production. Methods and Results - After a week of AF induced by rapid atrial pacing in pigs, O2 .- production from acutely isolated heart tissue was measured by 2 independent techniques, electron spin resonance and superoxide dismutase-inhibitable cytochrome C reduction assays. Compared with control animals with equivalent ventricular heart rates, basal O2 .- production was increased 2.7-fold (P<0.01) and 3.0-fold (P<0.02) in the LA and LAA, respectively. A similar 3.0-fold (P<0.01) increase in LAA O2 .- production was observed using a cytochrome C reduction assay. The increases could not be explained by changes in atrial total superoxide dismutase activity. Addition of either apocyanin or oxypurinol reduced LAA O2 .-, implying that NADPH and xanthine oxidases both contributed to increased O2 .- production in AF. Enzyme assays of atrial tissue homogenates confirmed increases in LAA NAD(P)H oxidase (P=0.04) and xanthine oxidase (P=0.01) activities. Although there were no changes in expression of the NADPH oxidase subunits, the increase in superoxide production was accompanied by an increase in GTP-loaded Rac1, an activator of the NADPH oxidase. Conclusions - AF increased O 2 .- production in both the LA and LAA. Increased NAD(P)H oxidase and xanthine oxidase activities contributed to the observed increase in LAA O2 .- production. This increase in O2 .- and its reactive metabolites may contribute to the pathological consequences of AF such as thrombosis, inflammation, and tissue remodeling.

Original languageEnglish (US)
Pages (from-to)1266-1273
Number of pages8
JournalCirculation
Volume112
Issue number9
DOIs
StatePublished - Aug 30 2005
Externally publishedYes

Fingerprint

Atrial Appendage
Xanthine Oxidase
NADPH Oxidase
Heart Atria
Superoxides
Atrial Fibrillation
Cytochromes
Superoxide Dismutase
Nitric Oxide
Thrombosis
Oxypurinol
Plasminogen Activator Inhibitor 1
Electron Spin Resonance Spectroscopy
Enzyme Assays
Guanosine Triphosphate
Embolism
Swine
Heart Rate
Stroke
Inflammation

Keywords

  • Atrium
  • Superoxide
  • Tachycardia

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

Cite this

Atrial fibrillation increases production of superoxide by the left atrium and left atrial appendage : Role of the NADPH and xanthine oxidases. / Dudley, Samuel C.; Hoch, Nyssa E.; McCann, Louise A.; Honeycutt, Clegg; Diamandopoulos, Laura; Fukai, Tohru; Harrison, David G.; Dikalov, Sergey I.; Langberg, Jonathan.

In: Circulation, Vol. 112, No. 9, 30.08.2005, p. 1266-1273.

Research output: Contribution to journalArticle

Dudley, SC, Hoch, NE, McCann, LA, Honeycutt, C, Diamandopoulos, L, Fukai, T, Harrison, DG, Dikalov, SI & Langberg, J 2005, 'Atrial fibrillation increases production of superoxide by the left atrium and left atrial appendage: Role of the NADPH and xanthine oxidases', Circulation, vol. 112, no. 9, pp. 1266-1273. https://doi.org/10.1161/CIRCULATIONAHA.105.538108
Dudley, Samuel C. ; Hoch, Nyssa E. ; McCann, Louise A. ; Honeycutt, Clegg ; Diamandopoulos, Laura ; Fukai, Tohru ; Harrison, David G. ; Dikalov, Sergey I. ; Langberg, Jonathan. / Atrial fibrillation increases production of superoxide by the left atrium and left atrial appendage : Role of the NADPH and xanthine oxidases. In: Circulation. 2005 ; Vol. 112, No. 9. pp. 1266-1273.
@article{8fa6f465add349b7950655ebb45d522f,
title = "Atrial fibrillation increases production of superoxide by the left atrium and left atrial appendage: Role of the NADPH and xanthine oxidases",
abstract = "Background - Atrial fibrillation (AF) is associated with an increased risk of stroke due almost exclusively to emboli from left atrial appendage (LAA) thrombi. Recently, we reported that AF was associated with endocardial dysfunction, limited to the left atrium (LA) and LAA and manifest as reduced nitric oxide (NO) production and increased expression of plasminogen activator inhibitor-1. We hypothesized that reduced LAA NO levels observed in AF may be associated with increased superoxide (O2 .-) production. Methods and Results - After a week of AF induced by rapid atrial pacing in pigs, O2 .- production from acutely isolated heart tissue was measured by 2 independent techniques, electron spin resonance and superoxide dismutase-inhibitable cytochrome C reduction assays. Compared with control animals with equivalent ventricular heart rates, basal O2 .- production was increased 2.7-fold (P<0.01) and 3.0-fold (P<0.02) in the LA and LAA, respectively. A similar 3.0-fold (P<0.01) increase in LAA O2 .- production was observed using a cytochrome C reduction assay. The increases could not be explained by changes in atrial total superoxide dismutase activity. Addition of either apocyanin or oxypurinol reduced LAA O2 .-, implying that NADPH and xanthine oxidases both contributed to increased O2 .- production in AF. Enzyme assays of atrial tissue homogenates confirmed increases in LAA NAD(P)H oxidase (P=0.04) and xanthine oxidase (P=0.01) activities. Although there were no changes in expression of the NADPH oxidase subunits, the increase in superoxide production was accompanied by an increase in GTP-loaded Rac1, an activator of the NADPH oxidase. Conclusions - AF increased O 2 .- production in both the LA and LAA. Increased NAD(P)H oxidase and xanthine oxidase activities contributed to the observed increase in LAA O2 .- production. This increase in O2 .- and its reactive metabolites may contribute to the pathological consequences of AF such as thrombosis, inflammation, and tissue remodeling.",
keywords = "Atrium, Superoxide, Tachycardia",
author = "Dudley, {Samuel C.} and Hoch, {Nyssa E.} and McCann, {Louise A.} and Clegg Honeycutt and Laura Diamandopoulos and Tohru Fukai and Harrison, {David G.} and Dikalov, {Sergey I.} and Jonathan Langberg",
year = "2005",
month = "8",
day = "30",
doi = "10.1161/CIRCULATIONAHA.105.538108",
language = "English (US)",
volume = "112",
pages = "1266--1273",
journal = "Circulation",
issn = "0009-7322",
publisher = "Lippincott Williams and Wilkins",
number = "9",

}

TY - JOUR

T1 - Atrial fibrillation increases production of superoxide by the left atrium and left atrial appendage

T2 - Role of the NADPH and xanthine oxidases

AU - Dudley, Samuel C.

AU - Hoch, Nyssa E.

AU - McCann, Louise A.

AU - Honeycutt, Clegg

AU - Diamandopoulos, Laura

AU - Fukai, Tohru

AU - Harrison, David G.

AU - Dikalov, Sergey I.

AU - Langberg, Jonathan

PY - 2005/8/30

Y1 - 2005/8/30

N2 - Background - Atrial fibrillation (AF) is associated with an increased risk of stroke due almost exclusively to emboli from left atrial appendage (LAA) thrombi. Recently, we reported that AF was associated with endocardial dysfunction, limited to the left atrium (LA) and LAA and manifest as reduced nitric oxide (NO) production and increased expression of plasminogen activator inhibitor-1. We hypothesized that reduced LAA NO levels observed in AF may be associated with increased superoxide (O2 .-) production. Methods and Results - After a week of AF induced by rapid atrial pacing in pigs, O2 .- production from acutely isolated heart tissue was measured by 2 independent techniques, electron spin resonance and superoxide dismutase-inhibitable cytochrome C reduction assays. Compared with control animals with equivalent ventricular heart rates, basal O2 .- production was increased 2.7-fold (P<0.01) and 3.0-fold (P<0.02) in the LA and LAA, respectively. A similar 3.0-fold (P<0.01) increase in LAA O2 .- production was observed using a cytochrome C reduction assay. The increases could not be explained by changes in atrial total superoxide dismutase activity. Addition of either apocyanin or oxypurinol reduced LAA O2 .-, implying that NADPH and xanthine oxidases both contributed to increased O2 .- production in AF. Enzyme assays of atrial tissue homogenates confirmed increases in LAA NAD(P)H oxidase (P=0.04) and xanthine oxidase (P=0.01) activities. Although there were no changes in expression of the NADPH oxidase subunits, the increase in superoxide production was accompanied by an increase in GTP-loaded Rac1, an activator of the NADPH oxidase. Conclusions - AF increased O 2 .- production in both the LA and LAA. Increased NAD(P)H oxidase and xanthine oxidase activities contributed to the observed increase in LAA O2 .- production. This increase in O2 .- and its reactive metabolites may contribute to the pathological consequences of AF such as thrombosis, inflammation, and tissue remodeling.

AB - Background - Atrial fibrillation (AF) is associated with an increased risk of stroke due almost exclusively to emboli from left atrial appendage (LAA) thrombi. Recently, we reported that AF was associated with endocardial dysfunction, limited to the left atrium (LA) and LAA and manifest as reduced nitric oxide (NO) production and increased expression of plasminogen activator inhibitor-1. We hypothesized that reduced LAA NO levels observed in AF may be associated with increased superoxide (O2 .-) production. Methods and Results - After a week of AF induced by rapid atrial pacing in pigs, O2 .- production from acutely isolated heart tissue was measured by 2 independent techniques, electron spin resonance and superoxide dismutase-inhibitable cytochrome C reduction assays. Compared with control animals with equivalent ventricular heart rates, basal O2 .- production was increased 2.7-fold (P<0.01) and 3.0-fold (P<0.02) in the LA and LAA, respectively. A similar 3.0-fold (P<0.01) increase in LAA O2 .- production was observed using a cytochrome C reduction assay. The increases could not be explained by changes in atrial total superoxide dismutase activity. Addition of either apocyanin or oxypurinol reduced LAA O2 .-, implying that NADPH and xanthine oxidases both contributed to increased O2 .- production in AF. Enzyme assays of atrial tissue homogenates confirmed increases in LAA NAD(P)H oxidase (P=0.04) and xanthine oxidase (P=0.01) activities. Although there were no changes in expression of the NADPH oxidase subunits, the increase in superoxide production was accompanied by an increase in GTP-loaded Rac1, an activator of the NADPH oxidase. Conclusions - AF increased O 2 .- production in both the LA and LAA. Increased NAD(P)H oxidase and xanthine oxidase activities contributed to the observed increase in LAA O2 .- production. This increase in O2 .- and its reactive metabolites may contribute to the pathological consequences of AF such as thrombosis, inflammation, and tissue remodeling.

KW - Atrium

KW - Superoxide

KW - Tachycardia

UR - http://www.scopus.com/inward/record.url?scp=24644499108&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=24644499108&partnerID=8YFLogxK

U2 - 10.1161/CIRCULATIONAHA.105.538108

DO - 10.1161/CIRCULATIONAHA.105.538108

M3 - Article

VL - 112

SP - 1266

EP - 1273

JO - Circulation

JF - Circulation

SN - 0009-7322

IS - 9

ER -