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- Title
Superoxide dismutase mimetic M40403 improves endothelial function in apolipoprotein(E)-deficient mice.
- Authors
Vonend, Oliver; Grote, Tobias; Oberhauser, Vitus; Ivar von Kügelgen; Rump, Lars Christian
- Abstract
1 Overproduction of superoxide anions in the vascular wall contributes to endothelial dysfunction in vascular disease. A superoxide-generating reduced β-nicotinamide adenine dinucleotide phosphate (NADPH) oxidase has recently been identified as a major source of oxidative radicals in vascular tissues. We studied the effects of a synthetic manganese-containing superoxide dismutase (SOD) mimetic, M40403. on NADPH oxidase-dependent superoxide generation and on endothelial dysfunction. 2 In rat aortic smooth muscle cells. NADPH (100 μM) markedly stimulated superoxide production as detected by lucigenin (5 μM)-enhanced chemiluminescence. M40403 reduced NADPH oxidase-dependent superoxide production in a concentration-dependent manner, with IC50 being 31.6 μM. In contrast, native Cu/Zn SOD (up to 300 U ml-1) had no effect. Angiotensin II (100 nM) increased the NADPH oxidase activity by 70%, and treatment with M40403 (10pM) reduced this increased superuxide to the control level. 3 In aortae from apolipoprotein(E)-delicient mice (apoE°) with hyperlipidemia and atherosclerosis, superoxide production is largely derived from NADPH oxidase. The attenuation of endothelial nitric oxide vasodilator function parallels the increase in vascular superoxide production at different stages of the disease. Acule incubation of such aortie rings with M40403 significantly suppressed superoxide production and improved endothelium-dependent vasorelaxation to a level comparable to that in wildtype control mice. 4 In summary, the cell-permeable SOD mimetic M40403 was found to reverse endothelial dysfunction in apoE° aorta ex vivo by decreasing NADPH oxidase-dependent superoxide levels. The advantages of synthetic SOD mimetics over the native Cu/Zn SOD enzyme, such as greater cell permeability and stability, confer significant therapeutic potential in vascular disease.
- Subjects
SUPEROXIDE dismutase; APOLIPOPROTEIN E; LABORATORY mice; BLOOD circulation; NITRIC oxide
- Publication
British Journal of Pharmacology, 2003, Vol 139, Issue 5, p1127
- ISSN
0007-1188
- Publication type
Article
- DOI
10. 1038/sj.bjp.0705354