Abstract 14535: NAD(P)H Oxidase-Ferived ROS Compensate for Reduced NO Bioavailability in MnSOD-Feficient, Hypercholesterolemic Mice
Reactive oxygen species (ROS) from both mitochondria and NAD(P)H oxidases modulate endothelial function, but the interaction between these two sources of ROS is poorly understood. We tested the hypothesis that increases in mitochondrial ROS, in hypercholesterolemic mice deficient in manganese superoxide dismutase (SOD2+/−), worsen endothelial dysfunction, in part through activation of NAD(P)H oxidase (i.e., ROS-induced ROS release) and a concomitant reduction in nitric oxide bioavailability. Endothelial function was examined in aorta from LDL receptor-deficient /Apolipoprotein B100/100 (LA) mice crossed with SOD2+/− mice. LA-SOD2+/+ and LA-SOD2+/− littermates were fed a Western diet for three months. In LA-SOD2+/+ mice relaxation to acetylcholine was modestly impaired (72.4 ± 2.0%). As expected, treatment with apocynin (NAD(P)H oxidase inhibitor) improved relaxation to acetylcholine slightly (78.2% ± 2.4, p < 0.05). In LA-SOD2+/− mice, impaired responses to acetylcholine were slightly greater compared to LA-SOD+/+ (difference in max relaxation = 3.8 ± 2.8%, p = n.s.). Surprisingly, however, treatment with apocynin dramatically reduced relaxation to acetylcholine in LA-SOD2+/− mice (from 68.5 ± 2.0 to 53.2% ± 3.0, p< .001). Relaxation to sodium nitroprusside was normal in both groups (> 95%), suggesting no differences in vascular sensitivity to nitric oxide. In conclusion, the data favor a working model in which the vasomotor effects of NAD(P)H oxidase are exquisitely context dependent. While ROS from NAD(P)H oxidase contribute to endothelial dysfunction when mitochondrial antioxidant defenses are intact, increases in NAD(P)H oxidase activity due to impaired mitochondrial antioxidant activity and ROS-induced ROS-release may paradoxically attenuate endothelial dysfunction in chronic, severe hypercholesterolemia mice.
- © 2010 by American Heart Association, Inc.