Published online before print January 10, 2002, doi: 10.1161/hh0302.104724
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Submitted on August 9, 2001
Revised on December 21, 2001
Accepted on December 21, 2001
Regression of Atherosclerosis in Monkeys Reduces Vascular Superoxide Levels
From the Department of Internal Medicine, University of Iowa College of Medicine and VA Medical Center, Iowa City, Iowa.
* To whom correspondence should be addressed. E-mail: francis-miller{at}uiowa.edu.
Superoxide (O2·-) in arteries may contribute to atherosclerosis in part by inactivation of nitric oxide. We hypothesized that regression of atherosclerosis in nonhuman primates is associated with a decrease in vascular NAD(P)H oxidase, decreased O2·- levels, and improved endothelium-dependent relaxation. Cynomolgus monkeys (n=28) were fed an atherogenic diet for 47±10 (mean±SE) months. In carotid arteries (containing advanced lesions), femoral arteries (moderate lesions), and saphena arteries (minimal lesions), we examined O2·- levels and vasomotor function. Compared with vessels from normal monkeys (n=8), O2·- levels (measured by lucigenin-enhanced chemiluminescence) were 3.3-fold higher in carotid, 1.7-fold higher in femoral, and not different in saphena arteries from atherosclerotic monkeys. Dihydroethidium staining also demonstrated increased O2·- levels throughout the vessel wall in femoral and carotid arteries from atherosclerotic monkeys. Components of the NAD(P)H oxidase (p22phox and p47phox) were increased in atherosclerotic arteries, and immunohistochemistry demonstrated colocalization primarily to areas of macrophage infiltration. Relaxation to acetylcholine was impaired in carotid and femoral, but not saphena, arteries from atherosclerotic monkeys. After 8 months of regression diet (n=9), serum cholesterol decreased to normal, and O2·- levels (basal and NAD(P)H-stimulated), as well as expression of NAD(P)H oxidase, returned toward normal. Relaxation to acetylcholine improved in femoral arteries, but not in the more diseased carotid arteries. We conclude that, in a primate model of moderately severe atherosclerosis and regression of atherosclerosis, changes in endothelial function are inversely related to O2·- and NAD(P)H oxidase levels. Reduction in vascular O2·- during regression of atherosclerosis may contribute to improvement in vasomotor function.
Key words: oxidative stress • vascular reactivity • blood vessels • macrophages • endothelium
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