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Effect of Aging, Mn‐SOD Deficiency, and Genetic Background on Endothelial Function: Evidence for Haploinsufficiency
Author(s) -
Brown Kathryn Ann,
Didion Sean P.,
Andresen Jon J.,
Faraci Frank M.
Publication year - 2006
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.20.4.a729-c
Subject(s) - superoxide dismutase , endothelial dysfunction , oxidative stress , superoxide , medicine , endocrinology , reactive oxygen species , endothelium , chemistry , dismutase , lucigenin , enzyme , biochemistry
Aging is associated with increased vascular superoxide and impaired endothelial function. We tested the hypothesis that Mn‐SOD is a key regulator of vascular oxidative stress with aging. We compared vascular function and superoxide levels in young (4–7 months) and old (22–24 months) wild‐type (Mn‐SOD +/+) and Mn‐SOD deficient (Mn‐SOD +/−) mice. We also determined if vascular changes with aging and Mn‐SOD status were influenced by genetic background (C57BL/6 versus CD1). Aortas from young Mn‐SOD +/+ (n=9), young Mn‐SOD +/− (n=6), old Mn‐SOD +/+ (n=9), and old Mn‐SOD +/− (n=14) mice on a C57BL/6 background were examined in vitro . Relaxation of aorta to the endothelium‐dependent dilator acetylcholine was similar in young Mn‐SOD +/+, young Mn‐SOD +/−, and old Mn‐SOD +/+, while responses were significantly impaired in old Mn‐SOD +/− mice; e.g. 100μM ACh produced 77±3 % (mean ± SE), 77±3 %, 70±4 % and 57±3 % relaxation in young Mn‐SOD +/+, young Mn‐SOD +/−, old Mn‐SOD +/+ and old Mn‐SOD +/− mice, respectively ( P <0.05). Superoxide levels, as measured using lucigenin (5 μM)‐enhanced chemiluminescence, were increased two‐fold in old Mn‐SOD +/− mice when compared to old Mn‐SOD +/+ and young mice ( P <0.05). These results provide the first evidence that Mn‐SOD functions to protect against increases in superoxide and endothelial dysfunction during aging, and this protection is not dependent on genetic background. Our results have implications for disease states or genetic polymorphisms that result in decreased expression of Mn‐SOD.