Role of superoxide in the pathogenesis of abdominal aortic aneurysms
iNOS ; NAD(P)H oxidase ; AAA ; superoxide ; abdominal aortic aneurysms
Increased superoxide (O2-) production may play important roles in the pathogenesis of aortic abdominal aneurysms (AAA). We have investigated sources of O2- in human AAA and its relationship to aneurysm diameter. O2- production was measured in AAA segments of from 40 patients undergoing AAA repair, using lucigenin enhanced chemiluminescence, and visualized by dihydroethidium (DHE) fluorescence. AAA diameter was determined in situ during the surgery. Malonylodialdehyde (MDA) levels were measured as a marker of oxidative stress from 16 patients with and 16 without AAA. MDA was higher in patient with AAA (4.87μM vs. 3.02μM; p<.02); Basal O2- production was observed in all AAA segments and was significantly higher than in nonAAA segments (23.2 vs. 12.9 RLU/s/mg; p<.001) Increased O2- production correlated with aneurysm diameter (r=.425; p=.038). O2- production was suppressed by preincubation with O2- scavenger Tiron or the superoxide dismutase. O2- production was significantly inhibited by iNOS inh.-1400W to 18% of control levels. O2- production was also significantly inhibited NAD(P)H oxidase inhibitors: diphenyliodonium to 16% or by apocynin to 51%. Modest inhibition (to 60%) was also observed in response to the cyclooxygenase inhibitor indomethacin. Inhibitors of other oxidase systems did not show significant effects. SOD inhibitable O2- production in AAA was localised mainly in ; media and adventitia, as shown by DHE staining. Addition of NADPH to intact AAAs segments increased of O2- production in AAA 19-fold. iNOS and NAD(P)H oxidase(s), are the predominant source of O2- production in AAA. Vascular O2- production is correlated with AAA diameter, as a measure of disease progression.