Rationale Oxidative stress has an important role in atrial fibrillation (AF)-induced myocardial remodelling, suggesting that specific oxidases may represent a novel therapeutic target in AF. Here we evaluated how the duration of AF affects the level, sources and localisation of superoxide.
Results and methods Our previous work in patients with predominantly paroxysmal AF showed that increased superoxide was produced by NOX2/NADPH oxidase. Here, in patients with permanent AF (n=26) versus matched controls in sinus rhythm (n=53), increased superoxide (assessed by lucigenin-enhanced chemiluminescence and 2-hydroxyethidum detection) was maintained by mitochondrial oxidases and ‘uncoupled’ nitric oxide synthase (NOS), but not NOX2/NADPH oxidase; although NOX4/NADPH oxidase was upregulated (real-time RT-PCR). Immunoblotting revealed increased protein expression of the mitochondrial complexes I–V and mitochondrial antioxidant peroxiredoxin-3; NOS ‘uncoupling’ was associated with reduced tetrahydropterin by 40% (BH4, HPLC).In the goat, after 14 days of AF, NADPH oxidase activity and protein expression were increased in the left atrium (LA). After 6 months of AF, superoxide release was doubled in both atria and originated from mitochondrial oxidases and ‘uncoupled’ NOS, which was associated with ipsilaterally reduced BH4 and increased arginase activity. Manganese superoxide dismutase was reduced by 50% at this stage.
Conclusion Activation of LA NOX2/NADPH oxidase occurs early in AF and is transient, since mitochondrial oxidases and ‘uncoupled’ NOS account for the increased superoxide production in permanent AF in both models. This suggests that NADPH oxidases may be a valuable target for ‘upstream’ treatment in short-term AF, but not once AF is established.
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