Abstract 10090: Small Mesenteric Arteries Are Resistant to Oxidative Stress Induced by eNOS Uncoupling in GTP-Cyclohydrolase I-Deficient Mice
Tetrahydrobiopterin (BH4) is an essential cofactor for endothelial nitric oxide synthase (eNOS). A number of reports have demonstrated that suboptimal levels of BH4 cause uncoupling of eNOS leading to reduced production of nitric oxide, elevated formation of superoxide anion and oxidative stress. Experiments were designed to test the hypothesis that long-term loss of BH4 exerts differential effect on large conduit and small resistance arteries. We used aorta and small mesenteric arteries (SMA) of male hph-1 mice, which displays GTP-cyclohydrolase I (GTPCH I) deficiency. Hph-1 mice were normotensive (122±2 mmHg vs. wild-type mice: 117±3 mmHg; n=5) and plasma cholesterol and blood glucose levels were not affected by genetic inactivation of GTPCH I. HPLC analysis revealed that enzymatic activity of GTPCH I was significantly reduced in aortas and SMA of hph-1 mice (0.15±0.03 pmol/mg/h and 0.57±0.14 pmol/mg/h, respectively; P<0.05 vs. wild-type mice: 0.32±0.05 pmol/mg/h and 1.87±0.60 pmol/mg/h, respectively; n=9-10). However, the ratio of BH4 to its oxidative products (7,8-dihydrobiopterin) was significantly increased only in the aorta of hph-1 mice (P<0.05; n=9-10). L-NAME sensitive superoxide anion production was significantly increased in aortas of hph-1 mice (0.56±0.12 nmol 2-hydroxyethidium/mg; P<0.05 vs. wild-type mice: 0.25±0.03 nmol/mg; n=7). In contrast, superoxide anion levels were unaltered in SMA of hph-1 mice (0.15±0.02 nmol 2-hydroxyethidium/mg; P<0.05 vs. wild-type mice: 0.14±0.01 nmol/mg; n=7). Interestingly, protein expression of copper- and zinc-containing superoxide dismutase (CuZnSOD) was significantly increased in SMA but not in aortas of hph-1 mice as compared with wild-type mice (P<0.05; n=4 and n=9, respectively). Expression of other SOD isoforms were unchanged in both blood vessel types (n=5-8). Our results demonstrate that adaptive increase in antioxidant capacity of SMA is responsible for resistance of arterial wall to eNOS uncoupling-induced oxidative stress. These findings indicate that anatomic origin and function of blood vessels determine their ability to cope with increased formation of superoxide anion generated by uncoupled eNOS.
- © 2011 by American Heart Association, Inc.