Cigarette smoke-induced proinflammatory alterations in the endothelial phenotype: role of NAD(P)H oxidase activation
Cigarette smoke-induced proinflammatory alterations in the endothelial phenotype: role of NAD(P)H oxidase activation
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DOI：
10.1152/ajpheart.00599.2006
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发表时间：
2007-01-01
影响因子：
4.8
通讯作者：
Ungvari, Zoltan
中科院分区：
文献类型：
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作者：
Orosz, Zsuzsanna;Csiszar, Anna;Ungvari, Zoltan
尽管吸烟引起的心血管发病率和死亡率超过肺癌，但吸烟引起血管损伤的分子基础仍不清楚。为了测试香烟烟雾、氧化应激和血管炎症之间的联系，大鼠暴露在每天五支香烟的烟雾中(持续1周)。用香烟烟雾提取物(CSE；0~40mU g/ml，作用6h)进行培养。我们发现吸烟可抑制乙酰胆碱引起的颈动脉松弛，NAD(P)H氧化酶抑制剂apocynin可改善这一作用。光亮素化学发光测量表明，吸烟和体外CSE暴露均显著增加血管O-2(中心点-)的产生。二氢乙啶染色显示内皮细胞和血管内皮细胞的O-2(中心点)生成增加。CSE还增加了血管过氧化氢的产生(二氯荧光素荧光)。吸烟和CSE暴露均可显著增加促炎细胞因子IL-1β、IL-6、TNF-α和诱导型一氧化氮合酶的表达，抑制NAD(P)H氧化酶(二苯基二碘和罗布麻素)或清除H_2O_2可阻止这一作用。在培养的内皮细胞中，CSE可诱导核因子-kappaB的激活，增加单核细胞的粘附性，这一作用可被apocynin和过氧化氢酶所阻止。因此，我们认为香烟烟雾的水溶性成分(可能存在于吸烟者体内的血液中)激活了血管中的NAD(P)H氧化酶。NAD(P)H氧化酶衍生的过氧化氢激活核因子-kappaB，导致血管表型的促炎性改变，这可能促进动脉粥样硬化的发展，特别是在其他危险因素存在的情况下。
Although the cardiovascular morbidity and mortality induced by cigarette smoking exceed those attributable to lung cancer, the molecular basis of smoking-induced vascular injury remains unclear. To test the link between cigarette smoke, oxidative stress, and vascular inflammation, rats were exposed to the smoke of five cigarettes per day (for 1 wk). Also, isolated arteries were exposed to cigarette smoke extract (CSE; 0 to 40 mu g/ml, for 6 h) in organoid culture. We found that smoking impaired acetylcholine-induced relaxations of carotid arteries, which could be improved by the NAD(P)H oxidase inhibitor apocynin. Lucigenin chemiluminescence measurements showed that both smoking and in vitro CSE exposure significantly increased vascular O-2(center dot-) production. Dihydroethidine staining showed that increased O-2(center dot-) generation was present both in endothelial and smooth muscle cells. CSE also increased vascular H2O2 production (dichlorofluorescein fluorescence). Vascular mRNA expression of the proinflammatory cytokines IL-1 beta, IL-6, and TNF-alpha and that of inducible nitric oxide synthase was significantly increased by both smoking and CSE exposure, which could be prevented by inhibition of NAD(P)H oxidase (diphenyleneiodonium and apocynin) or scavenging of H2O2. In cultured endothelial cells, CSE elicited NF-kappa B activation and increased monocyte adhesiveness, which were prevented by apocynin and catalase. Thus we propose that water-soluble components of cigarette smoke (which are likely to be present in the bloodstream in vivo in smokers) activate the vascular NAD(P)H oxidase. NAD(P)H oxidase-derived H2O2 activates NF-kappa B, leading to proinflammatory alterations in vascular phenotype, which likely promotes development of atherosclerosis, especially if other risk factors are also present.