Superoxide dismutase mimetic M40403 improves endothelial function in apolipoprotein(E)-deficient mice.
1. Overproduction of superoxide anions in the vascular wall contributes to endothelial dysfunction in vascular disease. A superoxide-generating reduced beta-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 micro M) markedly stimulated superoxide production as detected by lucigenin (5 micro M)-enhanced chemiluminescence. M40403 reduced NADPH oxidase-dependent superoxide production in a concentration-dependent manner, with IC(50) being 31.6 micro M. 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 (10 micro M) reduced this increased superoxide to the control level. 3. 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. 4. 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.
Jiang
Fan
F
Howard Florey Institute, The University of Melbourne, Victoria 3010, Australia. MetaPhore Pharmaceuticals, Inc., St Louis, MO, U.S.A.
Guo
Yanan
Y
Salvemini
Daniela
D
Dusting
Gregory J
GJ
D000818:Animals; D001013:Aorta, Thoracic; D001057:Apolipoproteins E / Q000172:deficiency* / Q000235:genetics*; D004305:Dose-Response Relationship, Drug; D042783:Endothelial Cells / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D016166:Free Radical Scavengers / Q000378:metabolism; D066298:In Vitro Techniques; D008297:Male; D008345:Manganese; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018716:Molecular Mimicry; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000201:enzymology; D009942:Organometallic Compounds / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013482:Superoxide Dismutase / Q000737:chemistry / Q000494:pharmacology*; D014664:Vasodilation / Q000187:drug effects / Q000502:physiology
D001057:Apolipoproteins E; D016166:Free Radical Scavengers; D009942:Organometallic Compounds; C121876:imisopasem manganese; D008345:Manganese; D013482:Superoxide Dismutase