Abstract 10885: Nox4 Nadph Oxidase Protects Against Load-Induced Cardiac Remodeling by Enhancing Myocardial Angiogenesis
Background: Reactive oxygen species (ROS) production is involved in the development of cardiac remodeling. NADPH oxidases are major ROS sources and cardiomyocytes express both Nox2 and Nox4. Nox2 is involved in load-induced cardiac hypertrophy and contractile dysfunction but the role of Nox4 is unknown. The aim of this study was to define the role of Nox4 in load-induced cardiac remodeling.
Results: Nox4 expression was low in normal heart but increased 4.7±0.8 fold after pressure overload (P<0.01). To investigate the relevance of increased Nox4 expression, we generated transgenic mice with cardiomyocyte-targeted increases in Nox4 (TG). TG had increased myocardial H2O2 levels (P<0.01) but no change in Nox2 levels. Cardiac function was unaltered in TG cf. wild-type littermates (WT) at age 2 or 12 months. After chronic aortic banding, TG had better preserved contractile function cf. WT by echocardiography or in vivo P-V analysis (eg, fractional shortening: 35.0±0.9 vs 27.7±1.0%; end-systolic elastance: 6.1±0.5 vs 4.3±0.5 mmHg/μl; both P<0.01). TG developed less hypertrophy than WT (LV/body weight ratio: 4.47±0.09 vs 5.33±0.28; P<0.01) and less LV dilatation (LV end-diastolic dimension: 0.41±0.01 vs 0.47±0.01 cm, P<0.01). To assess whether endogenous Nox4 had similar effects, we generated Nox4 knockout mice (KO). KO had no significant change in Nox2 levels and unaltered basal cardiac structure and function. After aortic banding, KO developed greater cardiac dysfunction and dilatation cf. WT (eg, ejection fraction: 33.2±1.3 vs 45.8±0.9%; LV end-diastolic volume: 95.1±7.4 vs 61.5±2.2 μl; P<0.01). Investigation of possible protective mechanisms revealed a significant Nox4-dependent preservation of myocardial capillary density after pressure overload which involved activation of Hif1 and enhanced release of VEGF.
Conclusions: Cardiomyocyte Nox4 is a novel inducible regulator of myocardial angiogenesis, a key determinant of cardiac adaptation to overload stress, and protects against load-induced cardiac remodeling. These effects are contrast markedly to those of Nox2, which contributes to cardiac dysfunction and hypertrophy. These results may provide an explanation for the failure of general antioxidant strategies in heart failure.
- Free radicals/Free-radical scavengers
- Cardiac hypertrophy
- Ventricular remodeling
- © 2010 by American Heart Association, Inc.