Abstract 1429: Critical Role of the NAD(P)H Oxidase Subunit p47phox for LV-Remodeling, -Dysfunction and Survival post-Myocardial Infarction
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). 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 post-MI remains to be determined.
Methods and Results: Myocardial infarction was induced in wild type (WT; n=46) and p47phox−/− deficient mice (n=32), 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 (83.0 ± 8.0 vs. 16.7 ± 3.5 nmol O2− x μg−1 x min−1; P<0.01), but not in p47phox deficient mice post-MI (13.5 ± 3.6 vs. 15.5 ± 3.5 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, but not in p47phox deficient mice post-MI. LV cavity dilatation and dysfunction 4 weeks post-MI were markedly attenuated in p47phox deficient mice as compared to WT mice as assessed by echocardiography (LV-EDD: 4.5 ± 0.2 vs. 6.3 ± 0.3 mm, P<0.01; ejection fraction 35.8 ± 2.5 vs. 22.6 ± 4.4 %; P<0.05). Furthermore, cardiomyocyte hypertrophy, interstitial fibrosis and cardiomyocyte apoptosis were substantially reduced in p47phox deficient mice as compared to WT mice. Importantly, the survival rate was markedly higher in p47phox deficient mice as compared to WT mice post-MI (72% vs. 48% ; P<0.05).
Conclusion: These results suggest a pivotal role of NAD(P)H oxidase activation and its subunit p47phox for LV-remodeling, -dysfunction and survival post-myocardial infarction. These findings support the concept that increased myocardial ROS production contributes importantly to LV-remodeling and dysfunction post-MI.