Superoxide production in vascular smooth muscle contributes to oxidative stress and impaired relaxation in atherosclerosis

FJ Miller, DD Gutterman, CD Rios, DD Heistad… - Circulation …, 1998 - Am Heart Assoc
FJ Miller, DD Gutterman, CD Rios, DD Heistad, BL Davidson
Circulation research, 1998Am Heart Assoc
The endothelium is a source of reactive oxygen species in short-term models of
hypercholesterolemia and atherosclerosis. We examined a chronic model of atherosclerosis
for increased vascular production of superoxide (O2−·) and determined whether endothelial
overexpression of superoxide dismutase (SOD) would improve endothelium-dependent
relaxation. Superoxide generation was 3 times higher in isolated aortas from Watanabe
heritable hyperlipidemic (WHHL) rabbits (2 to 4 years old) compared with aortas from New …
Abstract
—The endothelium is a source of reactive oxygen species in short-term models of hypercholesterolemia and atherosclerosis. We examined a chronic model of atherosclerosis for increased vascular production of superoxide (O2·) and determined whether endothelial overexpression of superoxide dismutase (SOD) would improve endothelium-dependent relaxation. Superoxide generation was 3 times higher in isolated aortas from Watanabe heritable hyperlipidemic (WHHL) rabbits (2 to 4 years old) compared with aortas from New Zealand White (NZ) rabbits (43±10 versus 14±2 relative light units · min−1 · mm−2, n=9, P<0.05). After in vitro transduction with adenovirus containing the gene for CuZn-SOD (AdCMVCuZn-SOD) or extracellular SOD (AdCMVEC-SOD), endothelial O2· levels in WHHL aortas were significantly reduced. Gene transfer of SOD to WHHL aortas, however, failed to improve the impaired relaxation to acetylcholine or calcium ionophore. By use of the oxidative fluorescent dye hydroethidine, an in situ assay indicated markedly increased generation of O2· throughout the wall of WHHL aorta, especially within layers of smooth muscle. This finding was confirmed by demonstrating increased O2· levels in smooth muscle cells cultured from WHHL aorta. We conclude that elevated O2· levels in atherosclerotic vessels are not confined to the endothelium but occur throughout the vascular wall, including smooth muscle cells. Reduction in endothelial O2· levels is not sufficient to improve endothelium-dependent relaxation. Generation of reactive oxygen species within the media may contribute to vasomotor dysfunction in atherosclerosis.
Am Heart Assoc