Document Detail

Regulation of the vascular extracellular superoxide dismutase by nitric oxide and exercise training.
MedLine Citation:
PMID:  10841522     Owner:  NLM     Status:  MEDLINE    
The bioactivity of endothelium-derived nitric oxide (NO) reflects its rates of production and of inactivation by superoxide (O(2)(*-)), a reactive species dismutated by extracellular superoxide dismutase (ecSOD). We have now examined the complementary hypothesis, namely that NO modulates ecSOD expression. The NO donor DETA-NO increased ecSOD expression in a time- and dose-dependent manner in human aortic smooth muscle cells. This effect was prevented by the guanylate cyclase inhibitor ODQ and by the protein kinase G (PKG) inhibitor Rp-8-CPT-cGMP. Expression of ecSOD was also increased by 8-bromo-cGMP, but not by 8-bromo-cAMP. Interestingly, the effect of NO on ecSOD expression was prevented by inhibition of the MAP kinase p38 but not of the MAP kinase kinase p42/44, suggesting that NO modulates ecSOD expression via cGMP/PKG and p38MAP kinase-dependent pathways, but not through p42/44MAP kinase. In aortas from mice lacking the endothelial nitric oxide synthase (eNOS), ecSOD was reduced more than twofold compared to controls. Treadmill exercise training increased eNOS and ecSOD expression in wild-type mice but had no effect on ecSOD expression in mice lacking eNOS, suggesting that this effect of exercise is meditated by endothelium-derived NO. Upregulation of ecSOD expression by NO may represent an important feed-forward mechanism whereby endothelial NO stimulates ecSOD expression in adjacent smooth muscle cells, thus preventing O(2)(*-)-mediated degradation of NO as it traverses between the two cell types.
T Fukai; M R Siegfried; M Ushio-Fukai; Y Cheng; G Kojda; D G Harrison
Publication Detail:
Type:  Journal Article; Research Support, U.S. Gov't, Non-P.H.S.; Research Support, U.S. Gov't, P.H.S.    
Journal Detail:
Title:  The Journal of clinical investigation     Volume:  105     ISSN:  0021-9738     ISO Abbreviation:  J. Clin. Invest.     Publication Date:  2000 Jun 
Date Detail:
Created Date:  2000-08-24     Completed Date:  2000-08-24     Revised Date:  2009-11-18    
Medline Journal Info:
Nlm Unique ID:  7802877     Medline TA:  J Clin Invest     Country:  UNITED STATES    
Other Details:
Languages:  eng     Pagination:  1631-9     Citation Subset:  AIM; IM    
Division of Cardiology, Department of Medicine, Emory University School of Medicine and the Atlanta Veterans Administration Hospital, Atlanta, Georgia 30322, USA.
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MeSH Terms
Aorta / enzymology
Mice, Inbred C57BL
Muscle, Smooth, Vascular / enzymology*
Nitric Oxide / physiology*
Nitric Oxide Synthase / physiology
Nitric Oxide Synthase Type II
Nitric Oxide Synthase Type III
Physical Conditioning, Animal*
RNA, Messenger / analysis
Superoxide Dismutase / biosynthesis*,  genetics
Superoxides / metabolism
Grant Support
Reg. No./Substance:
0/RNA, Messenger; 10102-43-9/Nitric Oxide; 11062-77-4/Superoxides; EC protein, human; EC Oxide Synthase; EC Oxide Synthase Type II; EC Oxide Synthase Type III; EC protein, mouse; EC Dismutase

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