Vascular effects of the human extracellular superoxide dismutase R213G variant

Article

关键词: HEPARIN-BINDING DOMAIN;    GENE-TRANSFER;    NITRIC-OXIDE;    EC-SOD;    HUMAN PLASMA;    AFFINITY;    RAT;    HYPERTENSION;    RELAXATION;    PRESSURE;   

DOI  :  10.1161/CIRCULATIONAHA.104.531251

来源: SCIE

【 摘 要 】

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 (ECSODR213G) was reported recently to be associated with ischemic heart disease. The goal of this study was to examine vascular effects of ECSODR213G. Methods and Results-A recombinant adenovirus (Ad) that expresses ECSODR213G was constructed. ECSODR213G and ECSOD proteins bound to collagen type I in vitro, but binding to aorta ex vivo was 10-fold greater with ECSOD than ECSODR213G. 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 ECSODR213G. Binding to aorta and carotid artery was 2.5- to 3-fold greater with ECSOD than ECSODR213G 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, ECSODR213G 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 ECSODR213G are predisposed to vascular diseases.

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