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Superoxide dismutase mimetic M40403 improves endothelial function in apolipoprotein(E)‐deficient mice
Author(s) -
Jiang Fan,
Guo Yanan,
Salvemini Daniela,
Dusting Gregory J
Publication year - 2003
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1038/sj.bjp.0705354
Subject(s) - superoxide , nadph oxidase , superoxide dismutase , nicotinamide adenine dinucleotide phosphate , apocynin , chemistry , lucigenin , angiotensin ii , oxidase test , reactive oxygen species , endothelium , biochemistry , endocrinology , medicine , oxidative stress , biology , enzyme , receptor
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. In rat aortic smooth muscle cells, NADPH (100 μ M ) markedly stimulated superoxide production as detected by lucigenin (5 μ M )‐enhanced chemiluminescence. M40403 reduced NADPH oxidase‐dependent superoxide production in a concentration‐dependent manner, with IC 50 being 31.6 μ M . In contrast, native Cu/Zn SOD (up to 300 U ml −1 ) had no effect. Angiotensin II (100 n M ) increased the NADPH oxidase activity by 70%, and treatment with M40403 (10 μ M ) reduced this increased superoxide to the control level. In aortae from apolipoprotein(E)‐deficient mice (apoE 0 ) 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. Acute incubation of such aortic rings with M40403 significantly suppressed superoxide production and improved endothelium‐dependent vasorelaxation to a level comparable to that in wildtype control mice. In summary, the cell‐permeable SOD mimetic M40403 was found to reverse endothelial dysfunction in apoE 0 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.British Journal of Pharmacology (2003) 139 , 1127–1134. doi: 10.1038/sj.bjp.0705354