Critical role of the NAD(P)H oxidase subunit p47phox for left ventricular remodeling/dysfunction and survival after myocardial infarction

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.