Atrial fibrillation increases production of superoxide by the left atrium and left atrial appendage - Role of the NADPH and xanthine oxidases
Atrial fibrillation increases production of superoxide by the left atrium and left atrial appendage - Role of the NADPH and xanthine oxidases
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DOI：
10.1161/circulationaha.105.538108
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发表时间：
2005-08-30
期刊：
影响因子：
37.8
通讯作者：
Langberg, J
中科院分区：
文献类型：
--
作者：
Dudley, SC;Hoch, NE;Langberg, J
背景——心房颤动（AF）与卒中风险增加相关，几乎完全是由于左心房附件（LAA）血栓栓塞所致。最近，我们报道了房颤与心内膜功能障碍有关，仅限于左心房（LA）和LAA，表现为一氧化氮（NO）的产生减少和纤溶酶原激活物抑制剂- 1的表达增加。我们假设降低LAA NO。在房颤中观察到的水平可能与超氧化物（O-2）增加有关。-))生产。方法与结果-猪快速心房起搏诱导AF 1周后，O-2(。-)通过电子自旋共振和超氧化物歧化酶抑制细胞色素C还原两种独立的技术来测量急性分离心脏组织的产量。与同等心室心率的对照动物相比，基础O-2(。-)产量分别提高2.7倍（P < 0.01）和3.0倍（P < 0.02）。LAA O-2升高3.0倍（P < 0.01）。用细胞色素C还原法观察生产。这种增加不能用心房总超氧化物歧化酶活性的变化来解释。添加apocyanin或oxypurinol均可降低LAA O-2(。-)，这意味着NADPH和黄嘌呤氧化酶都有助于O-2（）的增加。心房组织匀浆酶测定证实LAA - NAD(P) H氧化酶（P = 0.04）和黄嘌呤氧化酶（P = 0.01）活性增加。虽然NADPH氧化酶亚基的表达没有变化，但超氧化物产生的增加伴随着满载gtp的Rac1 （NADPH氧化酶的激活剂）的增加。结论：AF增加O-2(。-)在LA和LAA的生产。NAD(P) H氧化酶和黄嘌呤氧化酶活性升高导致LAA O-2（）升高。-)生产。O-2（）的增加。-)及其反应性代谢物可能导致房颤的病理后果，如血栓形成、炎症和组织重塑。
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 ( O-2(.-)) production.Methods and Results - After a week of AF induced by rapid atrial pacing in pigs, O-2(.-) 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 O-2(.-) 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 O-2(.-) 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 O-2(.-) , implying that NADPH and xanthine oxidases both contributed to increased O-2(.-) 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 O-2(.-) production. This increase in O-2(.-) and its reactive metabolites may contribute to the pathological consequences of AF such as thrombosis, inflammation, and tissue remodeling.