Downregulation of endocardial nitric oxide synthase expression and nitric oxide production in atrial fibrillation: potential mechanisms for atrial thrombosis and stroke.
BACKGROUND
In the arterial endothelium, laminar flow and cyclical stretch induce expression of NO synthase (NOS). We hypothesized that atrial fibrillation (AF) causes a downregulation of atrial endocardial NOS expression and NO* production. Because NO* has antithrombotic properties, this may contribute to thromboembolism in AF.


RESULTS
In pigs, AF was produced with rapid atrial pacing at 600 bpm for 1 week, whereas controls had atrial pacing at 100 bpm. All animals production from freshly isolated tissue was measured by a NO*-specific microelectrode. Left atrial basal and stimulated NO* production was decreased in AF by 73% and 71% (P<0.01). Endocardial NOS expression, determined by Western analysis, was also significantly decreased by 46%. Expression of the prothombotic protein plasminogen activator inhibitor 1 (PAI-1) is known to be regulated by NO* and was increased in the left atrium by 1.8-fold in AF (P<0.05). NO* concentration was decreased in the left atrial appendage, although NOS expression was not affected. Neither NOS concentration, NO* levels, nor PAI-1 expression were altered in the aortas or right atria of animals with AF.


CONCLUSIONS
AF is associated with a marked decrease in endocardial NOS expression and NO* bioavailability and an increase in PAI-1 expression in the left atrium. These data suggest that organized atrial contraction is needed to maintain normal endocardial expression of NOS. It is likely that loss of this antithrombotic enzyme contributes to the thromboembolic phenomena commonly observed in AF.
Cai
Hua
H
Division of Cardiology, Emory University School of Medicine, Atlanta, Ga, USA.
Li
Zongming
Z
Goette
Andreas
A
Mera
Fernando
F
Honeycutt
Clegg
C
Feterik
Kristian
K
Wilcox
Josiah N
JN
Dudley
Samuel C
SC
Harrison
David G
DG
Langberg
Jonathan J
JJ
D000818:Animals; D001281:Atrial Fibrillation / Q000378:metabolism* / Q000473:pathology; D015153:Blotting, Western; D002304:Cardiac Pacing, Artificial; D004195:Disease Models, Animal; D015536:Down-Regulation; D004562:Electrocardiography; D004699:Endocardium / Q000378:metabolism* / Q000473:pathology; D005260:Female; D006325:Heart Atria / Q000378:metabolism; D007150:Immunohistochemistry; D008297:Male; D009200:Myocardial Contraction; D009569:Nitric Oxide / Q000378:metabolism*; D019001:Nitric Oxide Synthase / Q000378:metabolism*; D017395:Plasminogen Activator Inhibitor 1 / Q000378:metabolism; D020521:Stroke / Q000209:etiology*; D013552:Swine; D013927:Thrombosis / Q000209:etiology*; D015854:Up-Regulation
D017395:Plasminogen Activator Inhibitor 1; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase