Zhang, Bin

Reduced antioxidant enzyme activity and subsequent impairments in endothelial function are major contributors to progression of atherosclerosis. We previously reported that endothelium‐dependent relaxation is well‐preserved in manganese superoxide dismutase‐deficient mice (MnSOD +/‐ ) due to production of a compensatory, H 2 O 2 ‐derived endothelial hyperpolarizing factor (EDHF). It is unclear, however, whether similar phenomena occur in hypercholesterolemic mice, and whether reconstitution of mitochondrial antioxidant capacity with mitochondria‐targeted antioxidants (mito‐Tempo) can reverse this phenomena. We used Ldlr ‐/‐ ApoB 100/100 (LA) mice that were either wild‐type (LA‐MnSOD +/+ ) or heterozygous (LA‐MnSOD +/‐ ) for MnSOD. After 6 months of Western diet, mice were treated with either saline (SAL) or MT (0.7mg/kg/day) using osmotic minipumps for 2 weeks. Endothelial function in aorta was assessed using isolated organ chamber baths in the presence or absence of apocynin (an NAD(P)H oxidase inhibitor, APO) . Osmotic minipump implantation significantly worsened baseline endothelial function compared to non‐implanted mice. Overall, relaxation to acetylcholine (MR ACH ) was unchanged between LA‐MnSOD +/+ and LA‐MnSOD +/‐ treated with SAL (3.8±4.5% and 13.6±14.5%, respectively). Treatment with MT significant improved endothelial function in LA‐MnSOD +/+ mice (21.6±7.1%), and MR ACH was further improved after acute incubation with APO (25±6.7%). In LA‐MnSOD +/‐ , MT greatly improved MR ACH (38.6±3.4%). In contrast to LA‐MnSOD +/+ , however, acute incubation of vessels with APO impaired MR ACH (27.3±10%). Collectively, our data suggest that increasing mitochondrial antioxidant capacity substantially improves endothelial function in hypercholesterolemic mice, but does not completely reverse compensatory molecular mechanisms that preserve endothelial function during prolonged mitochondrial antioxidant deficiency. NHLBI Grant Funding Source : Supported by NHLBI