Regression of atherosclerosis in monkeys reduces vascular superoxide levels
Regression of atherosclerosis in monkeys reduces vascular superoxide levels
复制标题
DOI：
10.1161/hh0302.104724
复制
发表时间：
2002-02-22
影响因子：
20.1
通讯作者：
Miller, FJ
中科院分区：
文献类型：
--
作者：
Hathaway, CA;Heistad, DD;Miller, FJ
动脉中的超氧化物 (O-2(.-)) 可能部分通过一氧化氮失活而导致动脉粥样硬化。我们假设非人灵长类动物动脉粥样硬化的消退与血管 NAD(P)H 氧化酶的减少、O-2(.-) 水平的降低和内皮依赖性舒张的改善有关。食蟹猴 (n=28) 被喂食致动脉粥样硬化饮食 47±10（平均 SE）个月。在颈动脉（包含晚期病变）、股动脉（中度病变）和隐动脉（轻微病变）中，我们检查了 O-2(.-) 水平和血管舒缩功能。与正常猴子 (n=8) 的血管相比，颈动脉中的 O-2(.-) 水平（通过光泽精增强化学发光测量）高出 3.3 倍，股动脉中高出 1.7 倍，而动脉粥样硬化猴的隐动脉中则没有差异。二氢乙锭染色还表明，动脉粥样硬化猴的股动脉和颈动脉中整个血管壁的 O-2(.-) 水平升高。动脉粥样硬化动脉中 NAD(P)H 氧化酶的成分（p22(phox) 和 p47(phox)）增加，免疫组织化学显示主要共定位于巨噬细胞浸润区域。动脉粥样硬化猴的颈动脉和股动脉（但隐动脉）对乙酰胆碱的舒张作用受损。经过 8 个月的回归饮食 (n=9)，血清胆固醇降至正常，O-2(.-) 水平（基础和 NAD(P)H 刺激）以及 NAD(P)H 氧化酶的表达恢复正常。乙酰胆碱的松弛作用改善了股动脉，但病变较严重的颈动脉却没有改善。我们的结论是，在中重度动脉粥样硬化和动脉粥样硬化消退的灵长类动物模型中，内皮功能的变化与 O-2(.-) 和 NAD(P)H 氧化酶水平呈负相关。动脉粥样硬化消退过程中血管 O-2(.-) 的减少可能有助于改善血管舒缩功能。
Superoxide (O-2(.-)) 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 O-2(.-) 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 O-2(.-) levels and vasomotor function. Compared with vessels from normal monkeys (n=8), O-2(.-) 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 O-2(.-) levels throughout the vessel wall in femoral and carotid arteries from atherosclerotic monkeys. Components of the NAD(P)H oxidase (p22(phox) and p47(phox)) 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 O-2(.-) 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 O-2(.-) and NAD(P)H oxidase levels. Reduction in vascular O-2(.-) during regression of atherosclerosis may contribute to improvement in vasomotor function.