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Increased superoxide leads to decreased flow-induced dilation in resistance arteries of Mn-SOD-deficient mice.

Yan C., Huang A., Wu Z., Kaminski P.M., Wolin M.S., Hintze T.H., Kaley G., Sun D.

The role of mitochondrial manganese-superoxide dismutase (Mn-SOD) in the maintenance of vascular function has not yet been studied. Thus we examined flow- and agonist-induced dilations in isolated mesenteric arteries (approximately 90 microm in diameter) of Mn-SOD heterozygous (Mn-SOD+/-) and wild-type (WT) mice. Increases in flow elicited dilations in all vessels, but the magnitude of the dilation was significantly less in vessels of Mn-SOD+/-mice than in those of WT mice (64 vs. 74% of passive diameter). N(omega)-nitro-L-arginine methyl ester inhibited the dilation in vessels of WT mice but had no effect on vessels of Mn-SOD+/-mice. Tempol or tiron (superoxide scavengers) increased flow-induced dilation in vessels of Mn-SOD+/- mice. Acetylcholine- and sodium nitroprusside-induced, but not adenosine-induced, dilations were also decreased in arteries of Mn-SOD+/-mice. Superoxide levels in the arteries of Mn-SOD+/-mice were significantly increased. Western blot analysis confirmed a 50% reduction of Mn-SOD protein in the vessels of Mn-SOD+/-mice. A 41% reduction in endothelial nitric oxide synthase (eNOS) protein and a 37% reduction in eNOS activity were also found in the vessels of Mn-SOD+/-mice. Whereas there was no difference in eNOS protein in kidney homogenates of WT and Mn-SOD+/-mice, a significant reduction of nitric oxide synthase activity was found in Mn-SOD+/-mice, which could be restored by the administration of tiron. We conclude that an increased concentration of superoxide due to reduced activity of Mn-SOD, which inactivates nitric oxide and inhibits eNOS activity, contributes to the impaired vasodilator function of isolated mesenteric arteries of Mn-SOD+/-mice. These results suggest that Mn-SOD contributes significantly to the regulation of vascular function.

Am. J. Physiol. Heart Circ. Physiol. 288:H2225-31(2005) [PubMed] [Europe PMC]

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