A myocardial Nox2 containing NAD(P)H oxidase contributes to oxidative stress in human atrial fibrillation.
Human atrial fibrillation (AF) has been associated with increased atrial oxidative stress. In animal models, inhibition of reactive oxygen species prevents atrial remodeling induced by rapid pacing, suggesting that oxidative stress may play an important role in the pathophysiology of AF. NAD(P)H oxidase is a major source of superoxide in the cardiovascular system; however, whether this enzyme contributes to atrial oxidative stress in AF remains to be elucidated. We investigated the sources of superoxide production (using inhibitors and substrates of a range of oxidases, RT-PCR, immunofluorescence, and immunoblotting) in tissue homogenates and isolated atrial myocytes from the right atrial appendage (RAA) of patients undergoing cardiac surgery (n=54 in sinus rhythm [SR] and 15 in AF). A membrane-bound gp91phox containing NAD(P)H oxidase in atrial myocytes was the main source of atrial superoxide production in SR and in AF. NADPH-stimulated superoxide release from RAA homogenates was significantly increased in patients with AF in the absence of changes in mRNA expression of the p22phox and gp91phox subunits of the NAD(P)H oxidase. In contrast with findings in SR patients, NO synthases (NOSs) contributed significantly to atrial superoxide production in fibrillating atria, suggesting that increased oxidative stress in AF may lead to NOS "uncoupling." These findings indicate that a myocardial NAD(P)H oxidase and, to a lesser extent, dysfunctional NOS contribute significantly to superoxide production in the fibrillating human atrial myocardium and may play an important role in the atrial oxidative injury and electrophysiological remodeling observed in patients with AF.
Kim
Young M
YM
University Department of Cardiovascular Medicine, John Radcliffe Hospital, Oxford, UK.
Guzik
Tomasz J
TJ
Zhang
Yin Hua
YH
Zhang
Mei Hua
MH
Kattach
Hassan
H
Ratnatunga
Chandi
C
Pillai
Ravi
R
Channon
Keith M
KM
Casadei
Barbara
B
D001281:Atrial Fibrillation / Q000378:metabolism*; D006801:Humans; D008562:Membrane Glycoproteins / Q000502:physiology*; D009206:Myocardium / Q000201:enzymology*; D032383:Myocytes, Cardiac / Q000378:metabolism; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases / Q000502:physiology*; D009569:Nitric Oxide / Q000096:biosynthesis; D019001:Nitric Oxide Synthase / Q000502:physiology; D018384:Oxidative Stress; D013481:Superoxides / Q000378:metabolism
D008562:Membrane Glycoproteins; D013481:Superoxides; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; C056558:CYBB protein, human; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases