First 11 pages of thesis. - OPUS - Universität Würzburg

under conditions of substrate or co-factor deficiency, nNOS uncouples to
generate superoxide 117, 121 . It was recently shown that induced expression of
nNOS in neuroepithelial cells 202 and over expression of nNOS in neuroblastoma
cells resulted in increased nNOS mediated superoxide formation 203 . These
results are consistent with our observation in atherosclerotic vessel where the
expression of nNOS is induced during atherosclerosis 164 .
4.3 iNOS generates nitric oxide and superoxide simultaneously
in apoE ko vessels
Our ESR measurements show that iNOS significantly contributes to nitric
oxide production in the vasculature of atherosclerotic apoE ko mice.
Interestingly, total aortic nitric oxide formation is increased in apoE ko,
compared to healthy wild type C57Bl6 mice. Vascular nitric oxide production in
apoE/iNOS dko mice was reduced to the levels of C57Bl6 mice, suggesting that
the source of increased nitric oxide production in apoE ko mice is iNOS. Since
iNOS is expressed in smooth muscle cells and leukocytes in the plaque, these
cell types mediate the additional aortic nitric oxide production 164 . iNOS is
regulated transcriptionally and catalyses the production of high concentrations
of nitric oxide, once the enzyme is expressed. In contrast, eNOS and nNOS
produce low amounts of nitric oxide in a highly regulated way.
Indirect measurements of nitric oxide like the L-arginine to L-citrulline
conversion assay and cGMP levels suggest that there is reduced eNOS
activity in atherosclerotic vessels 67 . The impaired endothelial nitric oxide
production results in impaired endothelial vasodilator function also termed
endothelial dysfunction. Therefore, atherosclerosis is generally considered a
- 72 -