Premium
Heterozygous Cu,Zn‐Superoxide Dismutase Deficiency Reveals a Vascular Phenotype with Aging
Author(s) -
Didion Sean P.,
Kinzenbaw Dale A.,
Schrader Laura I.,
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.20.5.a1452-d
Subject(s) - superoxide dismutase , medicine , endocrinology , superoxide , endothelial dysfunction , chemistry , reactive oxygen species , endothelium , wild type , oxidative stress , biology , enzyme , biochemistry , gene , mutant
The goal of the present study was to test the hypothesis that loss of a single gene for Cu,Zn‐superoxide dismutase (CuZnSOD) increases vascular superoxide and produces vascular dysfunction with aging. Responses of carotid arteries from young (6 months) and old (22–24 months of age) heterozygous CuZnSOD‐deficient (CuZnSOD+/−) mice and their wild‐type (CuZnSOD+/+) littermates were examined in vitro. Total SOD activity in aortic homogenates was reduced (P<0.05) by approximately a third in young CuZnSOD+/− mice as compared to wild‐type. Acetylcholine (ACh; an endothelium‐dependent agonist) produced similar concentration‐dependent relaxation (P>0.05) in carotid arteries from young wild‐type, young CuZnSOD+/− and old wild‐type mice. In contrast, relaxation to ACh was markedly impaired in old CuZnSOD+/− mice (eg, 100 μmol/L ACh produced 51±5 and 96±5% relaxation in vessels from old CuZnSOD+/− and old wild‐type mice, respectively). This effect was selective because relaxation to nitroprusside (an endothelium‐independent agonist) was similar (P>0.05) irrespective of age or CuZnSOD genotype. Responses to ACh in old CuZnSOD+/− mice were restored to normal following acute treatment with either tempol (a scavenger of superoxide; 1 mmol/L) or PJ34 (an inhibitor of poly‐ADP‐ribose polymerase (PARP); 3 μmol/L), suggesting that both superoxide and PARP activation contribute to endothelial dysfunction in CuZnSOD+/− mice with aging. These findings provide direct evidence that CuZnSOD expression protects endothelial function and that deficiency in a single copy of the CuZnSOD gene produces impairment of endothelial function with aging. These findings also have important implications for disease states and/or genetic polymorphisms that decrease activity of CuZnSOD.