Abstract 19995: p22phox-Based Nox4 Regulates Cellular Survival by Modulating FOXO3A Activity and Sirt1 Expression

Fasting triggers a survival response coordinated by the transcription factor FOXO3A and histone deacetylase SIRT1 by controlling the expression of antioxidant enzymes. We hypothesized that the NADPH oxidase Nox4 regulates these responses via FOXO3A-SIRT1 activation. We first decreased Nox4 or FOXO3A levels in human cardiac fibroblasts (HCFB) and measured apoptotic response induced by serum deprivation. Transfection with siNox4 caused a □300% increase in cellular apoptosis in response to serum deprivation. This was associated with a corresponding 50% increase in cellular H2O2 production (n=7, p<0.05). We hypothesized that oxidative stress caused by depletion of Nox4 or FOXO3A is due to downregulation of the antioxidant enzymes. Quantitative PCR analysis showed that deletion of Nox4 leads to downregulation of antioxidant enzymes catalase, peroxiredoxin III (Prx III) and the anti-apoptotic bcl2 while it triggered the upregulation of the pro-apoptotic factor Bim and atrogin1 in HCFB. Furthermore, the apoptoti...