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(Circulation Research. 2007;100:894.)
© 2007 American Heart Association, Inc.

Integrative Physiology

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

Carola Doerries, Karsten Grote, Denise Hilfiker-Kleiner, Maren Luchtefeld, Arnd Schaefer, Steven M. Holland, Sajoscha Sorrentino, Costantina Manes, Bernhard Schieffer, Helmut Drexler, Ulf Landmesser

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.

Correspondence to Ulf Landmesser, MD, Medizinische Hochschule Hannover, Abteilung Kardiologie und Angiologie, Carl Neuberg Str. 1, 30625 Hannover, Germany. 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 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 O₂^{– ·}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 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 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.

Key Words: myocardial infarction • remodeling • heart failure • NAD(P)H oxidase • superoxide anion

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