Peroxidase properties of extracellular superoxide dismutase role of uric acid in modulating in vivo activity

Objective - The cytosolic form of Cu/Zn-containing superoxide dismutase (SOD1) has peroxidase activity, with H₂O₂ used as a substrate to oxidize other molecules. We examined peroxidase properties of the extracellular form of SOD (SOD3), a major isoform of SOD in the vessel wall, by using recombinant SOD3 and an in vivo model of atherosclerosis. Methods and Results - In the presence of HCO₃^-, SOD3 reacted with H₂O₂ to produce a hydroxyl radical adduct of the spin trap 5-diethoxyphosphoryl-5methyl-1-pyrroline N-oxide (DEMPO). SOD1 and SOD3 were inactivated by H₂O₂ in a dose- and time-dependent fashion, and this was prevented by physiological levels of uric acid. To examine the in vivo role of uric acid on SOD1 and SOD3, control and apolipoprotein E-deficient (ApoE^-/-) mice were treated with oxonic acid, which inhibits urate metabolism. This treatment increased plasma levels of uric acid in control and ApoE^-/- mice by ≈3-fold. Although increasing uric acid levels did not alter aortic SOD1 and SOD3 protein expression, aortic SOD1 and SOD3 activities were increased by 2- to 3-fold in aortas from ApoE^-/- mice but not in aortas from control mice. Conclusions - These studies show that SOD1 and SOD3 are partially inactivated in atherosclerotic vessels of ApoE^-/- mice and that levels of uric acid commonly encountered in vivo may regulate vascular redox state by preserving the activity of these enzymes.