Published online before print March 1, 2007, doi: 10.1161/01.RES.0000261657.76299.ff
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Submitted on July 20, 2006
Revised on January 4, 2007
Accepted on February 19, 2007
Critical Role of the NAD(P)H Oxidase Subunit p47phox for Left Ventricular Remodeling/Dysfunction and Survival After Myocardial Infarction
Carola Doerries ;
From the Abteilung Kardiologie und Angiologie (C.D., K.G., D.H.-K., M.L., A.S., S.S., C.M., B.S., H.D., U.L.), Medizinische Hochschule Hannover, Germany; and Laboratory of Clinical Infectious Diseases (S.H.), National Institutes of Health, Bethesda, Md.
* To whom correspondence should be addressed. E-mail: Landmesser.Ulf{at}mh-hannover.de.
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 p47phox (p47phox-/- 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- ·µg-1·min-1; P<0.01) but not in p47phox-/- mice after MI (13.5±3.6 versus 15.5±3.5 nmol of O2- ·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 p47phox-/-, 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 p47phox-/- mice, after MI. LV cavity dilatation and dysfunction 4 weeks after MI were markedly attenuated in p47phox-/- 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 p47phox-/- mice as compared with WT mice. Importantly, the survival rate was markedly higher in p47phox-/- 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 p47phox 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.
Key words: myocardial infarction • remodeling • heart failure • NAD(P)H oxidase • superoxide anion
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