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Myocardial energetics and redox in health and disease
010 Cardiomyocyte-specific overexpression of Nox4 attenuates adverse cardiac remodelling after myocardial infarction
  1. M Zhang
  1. King's College London, BHF Centre of Excellence, The James Black Centre, London, UK

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Background

Reactive oxygen species (ROS) production is implicated in the development of cardiac remodelling after myocardial infarction (MI). NADPH oxidases are major sources of cardiovascular ROS, with cardiomyocytes expressing both Nox2 and Nox4 isoforms. We previously showed that Nox2 contributes significantly to the processes underlying adverse cardiac remodelling and contractile dysfunction post-MI, but the effect of Nox4 remains unclear. The aim of this study was to investigate the role of Nox4 in cardiac remodelling after MI.

Methods and Results

We generated transgenic mice with cardiomyocyte-specific overexpression of Nox4, expressing the mouse full-length Nox4 complimentary DNA under control of the α-MHC promoter. Transgenic mice were backcrossed onto a C57BL6/J background and wild-type littermates (wt) used as controls. Nox4 transgenic mice were grossly similar to wt in terms of body weight, growth, activity, fertility and basal cardiac function. Transgenic mice displayed heart-specific expression of the Nox4 transgene, had significantly higher Nox4 protein expression, over 60% higher heart NADPH oxidase activity and 42% increased hydrogen peroxide production (all p<0.05). Compared with wt, p22phox protein expression was increased by 2.4-fold, which may be related to an increased protein stability. There was no change in the protein expression level of Nox2 or eNOS. MI was achieved by permanent left coronary ligation for 4 weeks. Compared with wt/MI, transgenic/MI groups displayed significantly high survival rate (72% vs 95%) and less hypertrophy at 4 weeks post-MI in terms of heart/body weight ratio (6.95±0.16 vs 6.44±0.14, p<0.01), although the infarct size was similar (38.3±2.0% vs 39.9±2.8%). Transgenic mice also exhibited less apoptosis and interstitial cardiac fibrosis (0.52±0.03% vs 0.65±0.05%, p<0.05), and lower increases in the expression of fibronectin and procollagen III mRNA. Both echocardiography and cardiac catheterisation demonstrated less left ventricular cavity dilatation and a preservation of cardiac function in transgenic than wt mice.

Conclusions

In contrast to Nox2, which contributes to cardiac dilation, contractile dysfunction and fibrosis, cardiomyocyte Nox4 was found to exert protective effects against adverse remodelling post-MI.

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