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Effects of a common human gene variant of extracellular superoxide dismutase on endothelial function after endotoxin in mice
Author(s) -
Lund Donald D.,
Chu Yi,
Brooks Robert M.,
Faraci Frank M.,
Heistad Donald D.
Publication year - 2007
Publication title -
the journal of physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.802
H-Index - 240
eISSN - 1469-7793
pISSN - 0022-3751
DOI - 10.1113/jphysiol.2007.140830
Subject(s) - aorta , superoxide dismutase , extracellular , superoxide , lipopolysaccharide , chemistry , medicine , microbiology and biotechnology , endocrinology , biology , biochemistry , oxidative stress , enzyme
A common gene variant in the heparin‐binding domain (HBD) of extracellular superoxide dismutase (ECSOD) may predispose human carriers to ischaemic heart disease. We have demonstrated that the HBD of ECSOD is important for ECSOD to restore vascular dysfunction produced by endotoxin. The purpose of this study was to determine whether the gene variant in the HBD of ECSOD (ECSOD R213G ) protects against endothelial dysfunction in a model of inflammation. We constructed a recombinant adenovirus that expresses ECSOD R213G . Adenoviral vectors expressing ECSOD, ECSOD R213G or β‐galactosidase ( LacZ , a control) were injected i.v. in mice. After 3 days, at which time the plasma SOD activity is maximal, vehicle or endotoxin (lipopolysaccharide or LPS, 40 mg kg −1 ) was injected i.p. Vasomotor function of aorta in vitro was examined 1 day later. Maximal relaxation to sodium nitroprusside was similar in aorta from normal and LPS‐treated mice. Maximal relaxation to acetylcholine (10 −5 ) was impaired after LPS and LacZ (63 ± 3%, mean ± s.e.m. ) compared to normal vessels (83 ± 3%) ( P < 0.05). Gene transfer of ECSOD improved ( P < 0.05) relaxation in response to acetylcholine (76 ± 5%) after LPS, whereas gene transfer of ECSOD R213G had no effect (65 ± 4%). Superoxide was increased in aorta (measured using lucigenin and hydroethidine) after LPS, and levels of superoxide were significantly reduced following ECSOD but not ECSOD R213G . Thus, ECSOD reduces superoxide and improves relaxation to acetylcholine in the aorta after LPS, while the ECSOD variant R213G had minimal effect. These findings suggest that, in contrast to ECSOD, the common human gene variant of ECSOD fails to protect against endothelial dysfunction produced by an inflammatory stimulus.