Regulation of the vascular extracellular superoxide dismutase by nitric oxide and exercise training

Tohru Fukai, Martin R. Siegfried, Masuko Fukai, Yian Cheng, Georg Kojda, David G. Harrison

Research output: Contribution to journalArticle

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Abstract

The bioactivity of endothelium-derived nitric oxide (NO) reflects its rates of production and of inactivation by superoxide (O2·-), 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 O2·--mediated degradation of NO as it traverses between the two cell types.

Original languageEnglish (US)
Pages (from-to)631-1639
Number of pages1009
JournalJournal of Clinical Investigation
Volume105
Issue number11
StatePublished - Jun 1 2000
Externally publishedYes

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Superoxide Dismutase
Blood Vessels
Nitric Oxide
Exercise
Nitric Oxide Synthase Type III
Cyclic GMP-Dependent Protein Kinases
Mitogen-Activated Protein Kinase Kinases
Smooth Muscle Myocytes
Phosphotransferases
DEET
8-Bromo Cyclic Adenosine Monophosphate
Nitric Oxide Donors
Guanylate Cyclase
Protein Kinase Inhibitors
Superoxides
Aorta
Up-Regulation

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Regulation of the vascular extracellular superoxide dismutase by nitric oxide and exercise training. / Fukai, Tohru; Siegfried, Martin R.; Fukai, Masuko; Cheng, Yian; Kojda, Georg; Harrison, David G.

In: Journal of Clinical Investigation, Vol. 105, No. 11, 01.06.2000, p. 631-1639.

Research output: Contribution to journalArticle

Fukai, Tohru ; Siegfried, Martin R. ; Fukai, Masuko ; Cheng, Yian ; Kojda, Georg ; Harrison, David G. / Regulation of the vascular extracellular superoxide dismutase by nitric oxide and exercise training. In: Journal of Clinical Investigation. 2000 ; Vol. 105, No. 11. pp. 631-1639.
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