Downregulation of Endocardial Nitric Oxide Synthase Expression and Nitric Oxide Production in Atrial Fibrillation

Abstract

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. Methods and 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 had catheter ablation of the AV junction and ventricular pacing at 100 bpm. NO · 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.

Angiotensin type 1 receptor blockade prevents endocardial dysfunction of rapidly paced atria in rats

“…Figure 1a showed the representative recordings of the effects of olmesartan on the protein expression of TFPI, TM, eNOS and PAI-1 in the rapid pacing animal. While rapid atrial pacing for eight hours significantly decreased the concentrations of immunoreactive of TFPI, TM and eNOS proteins and increased the expression of PAI-1 as reported previously, 8,9 olmesartan significantly attenuated the magnitude of all these effects caused by rapid pacing (figure 1b, TFPI: p<0.0001 for both ANOVA and post-test for linear trend; TM: ANOVA, p=0.0094, and post-test for linear trend, p=0.0016; eNOS: ANOVA, p=0.0068, and post-test Figure 2 demonstrated the distribution of TFPI, TM, eNOS and PAI-1 proteins in the rapidlypaced left atrium with and without olmesartan at a dose of 3 mg/kg/day. As shown in our previous report and in others, 8,9 TFPI, TM and eNOS were predominantly expressed in the endocardial cells of the left atrium and apparently stripped by the rapid pacing.…”

Thrombomodulin and Tissue Factor Pathway Inhibitor in Endocardium of Rapidly Paced Rat Atria

“…Decreased laminar flow and hypercoagulable state of the blood have been emphasized as important involved mechanisms. However, a recent study, 6 for the first time, has reported the possible involvement of the endocardial dysfunction: AF decreased the nitric oxide synthase expression in the atrial endocardium. Our present results would also support this concept of endocardial dysfunction during AF.…”

Effect of Simvastatin and Antioxidant Vitamins on Atrial Fibrillation Promotion by Atrial-Tachycardia Remodeling in Dogs

“…These observations point to a role for factors other than Ca v 1.2 downregulation in contributing to atrial tachycardia-induced ERP changes and may be related to the observation that nitric oxide synthase downregulation with atrial tachycardia remodeling is more significant in the LA than in the RA. 35 Statins have pleiotropic effects, in addition to their antioxidant or antiinflammatory action, and the precise mechanisms of simvastatin action in tachycardia remodeling remain to be established.…”