P112	Role of the NAD(P)H oxidase subunit p47phox for LV-remodeling, -dysfunction and survival post-myocardial infarction.
C.Dörries, K.Grote, D.Hilfiker-Kleiner, M.Luchtefeld, A.Schaefer, S.A.Sorrentino, B.Schieffer, H.Drexler, U.Landmesser
Department of Cardiology and Angiology, Medical School of Hannover, Hannover, DE.

Background: Accumulating evidence suggests a critical role of increased reactive oxygen species (ROS) production for left ventricular (LV) remodeling and dysfunction post-myocardial infarction (MI). Moreover, increased myocardial activity of the NAD(P)H oxidase, a major oxidant enzyme system, has been observed in clinical heart failure, however, a potential role of the NAD(P)H oxidase for LV-remodeling processes post-MI remains to be determined. Methods and Results: Myocardial infarction was induced in wild type (WT; n=46) and p47phox-/- deficient mice (n=30), lacking the cytosolic NAD(P)H oxidase component p47phox. Infarct size was similar among the groups. NAD(P)H oxidase activity was markedly increased in remote LV-myocardium of WT mice post-MI as compared to sham-operated mice (55±11 vs. 23±5 nmol O2- x µg-1 x min-1; P<0.05), but not in p47phox deficient mice post-MI (13±2 vs. 15±2 nmol O2- x µg-1 x min-1), as assessed by electron spin resonance (ESR) spectroscopy using the spin trap CP-H. Myocardial ROS production was increased in WT mice post-MI, but not in p47phox deficient mice. LV cavity dilatation and dysfunction 4 weeks post-MI was markedly attenuated in p47phox-deficient mice as compared to WT mice as assessed by echocardiography (LV-EDD: 4.6±0.2 vs. 6.3±0.3 mm, P<0.05; LV-ejection fraction 37.7±2.9 vs. 22.6±4.2 %; P<0.05). Furthermore, myocardial hypertrophy and interstitial fibrosis were substantially reduced in p47phox deficient mice as compared to WT mice post-MI. Importantly, in p47phox deficient mice the survival rate post-MI was markedly higher as compared to WT mice (73 vs. 47 % ; P<0.05). Conclusion: These results suggest an important role of NAD(P)H oxidase activation and its subunit p47phox for LV-remodeling, -dysfunction and survival post-myocardial infarction. The present findings thereby support the concept that increased myocardial ROS production contributes to LV remodeling processes post-MI.

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