Vascular effects of the human extracellular superoxide dismutase R213G variant.
BACKGROUND
Extracellular superoxide dismutase (ECSOD) is a major extracellular antioxidant enzyme. We have demonstrated that vascular effects of ECSOD require an intact heparin-binding domain. A common genetic variant with a substitution in the heparin-binding domain (ECSOD(R213G)) was reported recently to be associated with ischemic heart disease. The goal of this study was to examine vascular effects of ECSOD(R213G).


RESULTS
A recombinant adenovirus (Ad) that expresses ECSOD(R213G) was constructed. ECSOD(R213G) and ECSOD proteins bound to collagen type I in vitro, but binding to aorta ex vivo was 10-fold greater with ECSOD than ECSOD(R213G). Three days after intravenous injection of AdECSOD(R213G) or AdECSOD in spontaneously hypertensive rats (SHR), immunostaining demonstrated binding of ECSOD to carotid arteries and kidneys but minimal binding of ECSOD(R213G). Binding to aorta and carotid artery was 2.5- to 3-fold greater with ECSOD than ECSOD(R213G) by immunoblotting. Arterial pressure was significantly reduced by AdECSOD but not by AdECSOD(R213G). Responses to acetylcholine and basal levels of nitric oxide in carotid arteries were impaired in SHR compared with normotensive Wistar-Kyoto rats and were improved after AdECSOD but not AdECSOD(R213G). Levels of superoxide and nitrotyrosine in aorta were higher in SHR than Wistar-Kyoto rats and were greatly reduced after AdECSOD but not AdECSOD(R213G).


CONCLUSIONS
In contrast to ECSOD, ECSOD(R213G) has no significant protective effect on arterial pressure, vascular function, or vascular levels of oxidative stress in SHR. These findings may provide a mechanistic basis for association studies that suggest that human beings carrying ECSOD(R213G) are predisposed to vascular diseases.
Chu
Yi
Y
Cardiovascular Center, Department of Internal Medicine, University of Iowa, Roy J and Lucille A. Carver College of Medicine, Iowa City, IA 52242, USA.
Alwahdani
Abdullah
A
Iida
Shinichiro
S
Lund
Donald D
DD
Faraci
Frank M
FM
Heistad
Donald D
DD
D019943:Amino Acid Substitution; D000818:Animals; D001120:Arginine; D003928:Diabetic Nephropathies / Q000235:genetics; D004195:Disease Models, Animal; D018014:Gene Transfer Techniques; D005998:Glycine; D006801:Humans; D007676:Kidney Failure, Chronic / Q000235:genetics / Q000401:mortality / Q000628:therapy; D008297:Male; D017202:Myocardial Ischemia / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D011994:Recombinant Proteins / Q000494:pharmacology; D013482:Superoxide Dismutase / Q000235:genetics*
D011994:Recombinant Proteins; D001120:Arginine; C441642:SOD3 protein, human; D013482:Superoxide Dismutase; D005998:Glycine