Endothelial nitric oxide synthase in vascular disease -: From marvel to menace
Endothelial nitric oxide synthase in vascular disease -: From marvel to menace
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DOI：
10.1161/circulationaha.105.602532
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发表时间：
2006-04-04
期刊：
影响因子：
37.8
通讯作者：
Münzel, T
中科院分区：
文献类型：
--
作者：
Förstermann, U;Münzel, T
一氧化氮（NO中心点）是血管系统中重要的保护分子，内皮NO中心点合酶（eNOS）负责大部分血管NO中心点的产生。功能性 eNOS 将其底物 L-精氨酸氧化为 L-瓜氨酸和 NO 中心点。 eNOS 的这种正常功能需要酶的二聚化、底物 L-精氨酸和必需辅因子 (6R)-5,6,7,8-四氢-L-生物蝶呤 (BH4)（最有效的天然还原剂之一）的存在。高血压、高胆固醇血症、糖尿病或长期吸烟等心血管危险因素会刺激血管壁中活性氧的产生。烟酰胺腺嘌呤二核苷酸磷酸 (NADPH) 氧化酶是这种活性氧的主要来源，并且已发现在高血压、糖尿病和久坐生活方式的动物模型以及患有心血管危险因素的患者中上调和激活。超氧化物（O-2（中心点-））与血管NO中心点发生强烈反应，形成过氧亚硝酸盐（ONOO-）。辅因子 BH4 对 ONOO- 的氧化高度敏感。 BH4 水平的降低促进 eNOS 产生 O-2（中心点-）（称为 eNOS 解偶联）。在一些体外模型、心血管疾病动物模型以及患有心血管危险因素的患者中观察到了 eNOS 从保护性酶向氧化应激贡献者的转变。在许多情况下，补充 BH4 已被证明可以纠正动物模型和患者的 eNOS 功能障碍。此外，叶酸和维生素 C 的输注也能够恢复 eNOS 功能，很可能是通过提高 BH4 水平来恢复的。
Nitric oxide (NO center dot) is an important protective molecule in the vasculature, and endothelial NO center dot synthase (eNOS) is responsible for most of the vascular NO center dot produced. A functional eNOS oxidizes its substrate L-arginine to L-citrulline and NO center dot. This normal function of eNOS requires dimerization of the enzyme, the presence of the substrate L-arginine, and the essential cofactor (6R)-5,6,7,8-tetrahydro-L-biopterin (BH4), one of the most potent naturally occurring reducing agents. Cardiovascular risk factors such as hypertension, hypercholesterolemia, diabetes mellitus, or chronic smoking stimulate the production of reactive oxygen species in the vascular wall. Nicotinamide adenine dinucleotide phosphate (NADPH) oxidases represent major sources of this reactive oxygen species and have been found upregulated and activated in animal models of hypertension, diabetes, and sedentary lifestyle and in patients with cardiovascular risk factors. Superoxide (O-2(center dot-)) reacts avidly with vascular NO center dot to form peroxynitrite (ONOO-). The cofactor BH4 is highly sensitive to oxidation by ONOO-. Diminished levels of BH4 promote O-2(center dot-) production by eNOS (referred to as eNOS uncoupling). This transformation of eNOS from a protective enzyme to a contributor to oxidative stress has been observed in several in vitro models, in animal models of cardiovascular diseases, and in patients with cardiovascular risk factors. In many cases, supplementation with BH4 has been shown to correct eNOS dysfunction in animal models and patients. In addition, folic acid and infusions of vitamin C are able to restore eNOS functionality, most probably by enhancing BH4 levels as well.