Abstract 534: Superoxide Dismutase 1 Modulates STAT3 pathway in Angiotensin II Induced Vascular Remodeling

Abstract

[Background] Superoxide dismutase 1 (copper/zinc SOD; SOD-1) generates hydrogen peroxide (H2O2) from superoxide and is predominantly expressed in cytosol of vascular walls. Angiotensin II (Ang-II) induces vascular remodeling is associated with H2O2 generation from NADPH oxidase. We have previously shown that SOD-1 modulates Ang-II induced vascular remodeling. The aim of this study is to seek the signaling mechanisms for SOD-1to modulate vascular remodeling with Ang-II in in vivo. [Methods and Results] We employed SOD-1 deficient mice (SOD-1-/-), which were continuously infused with Ang-II (3.2mg/kg/day) for seven days. There was no difference in blood pressure between SOD-1-/- and their wild-type mice (WT). The serum levels of derivatives of reactive oxygen metabolites were similarly increased in both WT and SOD-1-/- with Ang-II, however, an increase in oxidized glutathione levels in whole blood cells were blunted in SOD-1-/-, suggesting a decrease in cytosolic H2O2 generations with SOD-1 deficiency. In histological analysis, Ang-II increased aortic wall thicknesses in WT, however, the responses were also blunted in SOD-1-/- (wild-type: 91.9±3.0μm SOD-1-/-: 68.4±4.5μm, P<0.001, N=10-12). In western blot analysis, Ang-II infusion enhanced the phosphorylation of signal-transducer-and-activator-of-transcription 3 (STAT3) in aortas from WT, which was blunted in SOD-1-/-, while the phosphorylation of ERK and Akt were identical. The interleukin 6 (IL-6) of serums were equally elevated in both SOD-1-/- and WT with Ang-II infusion. In cultured rat vascular smooth muscle cells (VSMCs), Ang II (24 h) slowly increased, and IL-6 (5 min) or hydrogen peroxide (H2O2) (15min) rapidly increased the phosphorylation of STAT3. With copper-chelating agents (N, N-diethyldithiocarbamate; 1mM 4h), the phosphorylation of STAT3 was blunted with all agonists. [Conclusion] These results indicated that the activation of STAT3 plays a role in Ang II- induced vascular remodeling, and SOD-1 is involved with the signaling mechanism in in vitro and in vivo.