Critical role of the NAD(P)H oxidase subunit p47phox for left ventricular remodeling/dysfunction and survival after myocardial infarction
Critical role of the NAD(P)H oxidase subunit p47phox for left ventricular remodeling/dysfunction and survival after myocardial infarction
复制标题
DOI：
10.1161/01.res.0000261657.76299.ff
复制
发表时间：
2007-03-30
影响因子：
20.1
通讯作者：
Landmesser, Ulf
中科院分区：
文献类型：
--
作者：
Doerries, Carola;Grote, Karsten;Landmesser, Ulf
越来越多的证据表明，活性氧的产生增加的左心室（LV）重构和功能障碍后，心肌梗死（MI）的关键作用。在人心力衰竭中观察到NAD（P）H氧化酶（一种主要氧化酶系统）的心肌活性增加;然而，NAD（P）H氧化酶在MI后LV重塑和功能障碍中的作用仍有待确定。在野生型（WT）小鼠（n = 46）和缺乏胞质NAD（P）H氧化酶组分p47（phox）的小鼠（p47（phox-/-）小鼠）（n = 32）中诱导MI。各组间的颅内压大小相似。与假手术小鼠相比，MI后WT小鼠远端LV心肌中NAD（P）H氧化酶活性显著增加（83 +/- 8 vs 16.7 +/- 3.5 nmol O-2（-.）.μ g（-1）.min（-1）; P < 0.01），但在MI后的p47（phox-/-）小鼠中没有（13.5 +/- 3.6对15.5 +/- 3.5 nmol O2（-.）μ g（-1）.min（-1）），如通过使用自旋探针CP-H的电子自旋共振光谱法所评估的。此外，在WT中观察到心肌黄嘌呤氧化酶活性增加，但在MI后的p47（phox-/-）小鼠中未观察到，表明NAD（P）H氧化酶依赖性黄嘌呤氧化酶活化。心肌梗死后，WT小鼠的心肌活性氧产生增加，但p47（phox-/-）小鼠没有。通过超声心动图评估，与WT小鼠相比，MI后4周，p47（phox-/-）小鼠的LV腔扩张和功能障碍明显减弱（左室舒张末期直径：4.5 ± 0.2 mm vs 6.3 ± 0.3 mm，P < 0.01;左室射血分数：35.8 ± 2.5% vs 22.6 ± 4.4%，P < 0.05）。此外，与WT小鼠相比，p47（phox-/-）小鼠的心肌细胞肥大、凋亡和间质纤维化显著减少。重要的是，MI后p47（phox-/-）小鼠的存活率显著高于WT小鼠（72%对48%; P < 0.05）。这些结果表明，NAD（P）H氧化酶活化及其亚基p47（phox）对MI后LV重构/功能障碍和存活率具有关键作用。因此，NAD（P）H氧化酶系统代表了预防MI后心力衰竭的潜在新治疗靶点。
Accumulating evidence suggests a critical role of increased reactive oxygen species production for left ventricular ( LV) remodeling and dysfunction after myocardial infarction ( MI). An increased myocardial activity of the NAD( P) H oxidase, a major oxidant enzyme system, has been observed in human heart failure; however, the role of the NAD( P) H oxidase for LV remodeling and dysfunction after MI remains to be determined. MI was induced in wild-type ( WT) mice ( n = 46) and mice lacking the cytosolic NAD( P) H oxidase component p47(phox) ( p47(phox-/-) mice) ( n = 32). Infarct size was similar among the groups. NAD( P) H oxidase activity was markedly increased in remote LV myocardium of WT mice after MI as compared with sham-operated mice ( 83 +/- 8 versus 16.7 +/- 3.5 nmol of O-2(-.) . mu g(-1).min(-1); P < 0.01) but not in p47(phox-/-) mice after MI ( 13.5 +/- 3.6 versus 15.5 +/- 3.5 nmol of O2(-.) mu g(-1).min(-1)), as assessed by electron-spin resonance spectroscopy using the spin probe CP-H. Furthermore, increased myocardial xanthine oxidase activity was observed in WT, but not in p47(phox-/-) mice after MI, suggesting NAD( P) H oxidase - dependent xanthine oxidase activation. Myocardial reactive oxygen species production was increased in WT mice, but not in p47(phox-/-) mice, after MI. LV cavity dilatation and dysfunction 4 weeks after MI were markedly attenuated in p47(phox-/-) mice as compared with WT mice, as assessed by echocardiography ( LV end-diastolic diameter: 4.5 +/- 0.2 versus 6.3 +/- 0.3 mm, P < 0.01; LV ejection fraction, 35.8 +/- 2.5 versus 22.6 +/- 4.4%, P < 0.05). Furthermore, cardiomyocyte hypertrophy, apoptosis, and interstitial fibrosis were substantially reduced in p47(phox-/-) mice as compared with WT mice. Importantly, the survival rate was markedly higher in p47(phox-/-) mice as compared with WT mice after MI ( 72% versus 48%; P < 0.05). These results suggest a pivotal role of NAD( P) H oxidase activation and its subunit p47(phox) for LV remodeling/ dysfunction and survival after MI. The NAD( P) H oxidase system represents therefore a potential novel therapeutic target to prevent cardiac failure after MI.