Critical Role of the NAD(P)H Oxidase Subunit p47 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 (p47 / 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 O2 g 1 min ; P 0.01) but not in p47 / mice after MI (13.5 3.6 versus 15.5 3.5 nmol of O2 g 1 min ), 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 / 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 / mice, after MI. LV cavity dilatation and dysfunction 4 weeks after MI were markedly attenuated in p47 / 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 / mice as compared with WT mice. Importantly, the survival rate was markedly higher in p47 / 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 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. (Circ Res. 2007;100:894-903.)