Critical Role of the NAD(P)H Oxidase Subunit p47 phox for Left Ventricular Remodeling/Dysfunction and Survival After Myocardial Infarction

Abstract

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 − · μg −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 O 2 − · μg −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.