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.


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 approximately 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.
Hink
H Ulrich
HU
Division of Cardiology, Department of Medicine, Emory University School of Medicine, Atlanta, Ga 30322, USA.
Santanam
Nalini
N
Dikalov
Sergey
S
McCann
Louise
L
Nguyen
Andrew D
AD
Parthasarathy
Sampath
S
Harrison
David G
DG
Fukai
Tohru
T
D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency / Q000502:physiology; D001161:Arteriosclerosis / Q000201:enzymology; D001639:Bicarbonates / Q000378:metabolism; D005110:Extracellular Space / Q000201:enzymology*; D006861:Hydrogen Peroxide / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D009195:Peroxidase / Q000378:metabolism*; D010843:Pichia / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D019097:Spin Trapping / Q000379:methods; D013379:Substrate Specificity; D013482:Superoxide Dismutase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000072105:Superoxide Dismutase-1; D014162:Transfection; D014527:Uric Acid / Q000097:blood / Q000378:metabolism*
D001057:Apolipoproteins E; D001639:Bicarbonates; D011994:Recombinant Proteins; D014527:Uric Acid; D006861:Hydrogen Peroxide; D009195:Peroxidase; C000606291:Sod1 protein, mouse; C499090:Sod3 protein, mouse; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1