Abstract 17291: Superoxide Dismutase-1 Regulates the Vascular Inflammation, via Local Interleukin 6 Productions
Background: Superoxide dismutase-1 (SOD-1) generates hydrogen peroxide (H2O2) from superoxide and is predominantly expressed in cytosol of vascular walls. Angiotensin II (Ang-II) induces vascular remodeling, which is associated with superoxide/H2O2 generation from various NADPH oxidase isoforms (NOX). We have previously shown that SOD-1 modulates Ang-II-induced vascular remodeling without changing hypertensive responses. The aim of this study is to clarify the role of SOD-1 in the modulation of vascular inflammation induced 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 systolic blood pressure between both mice with Ang-II, however, the aortic wall thicknesses by Ang-II were 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 unchanged. Although the serum interleukin 6 (IL-6) levels were equally elevated in both mice with Ang-II infusion, the expression of vascular IL-6, which was assessed with real-time PCR, was elevated not in SOD-1-/- but only in WT with Ang-II infusion. The expression of IL-1β, MCP-1 as well as NOX2 were induced in aorta from WT with Ang-II, which were blunted in aorta from SOD-1-/-. In cultured vascular smooth muscle cells (VSMCs) from rats, Ang-II (24 h) slowly increased the IL-6 releases and the phosphorylation of STAT3. The phosphorylation of STAT3 with Ang-II was blunted in VSMC pre-treated with siRNA of SOD-1, although the rapid phosphorylation of STAT3 with IL-6 (5 min) was maintained in in vitro.
Conclusion: These results showed that SOD-1 played a critical role in vascular IL-6 productions and STAT3 activation with Ang-II infusion. These signaling events induced the vascular inflammation and oxidative stress, associated with the up-regulation of MCP-1, IL-1β, and NOX2. The pro-inflammatory role of SOD-1 can contribute to the vascular remodeling induced with Ang-II in in vivo.
- © 2013 by American Heart Association, Inc.