Cirillo Plinio, Pacileo Mario, De Rosa Salvatore, Calabrò Paolo, Gargiulo Annarita, Angri Valeria, Prevete Nella, Fiorentino Isabella, Ucci Grazia, Sasso Laura, Petrillo Gianluca, Musto D'Amore Sergio, Chiariello Massimo
Division of Cardiology, University of Naples Federico II, Naples, Italy.
J Vasc Res. 2007;44(6):460-70. doi: 10.1159/000106464. Epub 2007 Jul 26.
Smoking predisposes to the development of atherosclerosis and of its complications. The mechanisms responsible for these effects are not completely understood. We have investigated whether nicotine might promote a proatherosclerotic state in human coronary endothelial cells (HCAECs), studying the role of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors in preventing these phenomena.
Real-time PCR showed that nicotine induced a dose-dependent increase in mRNA levels for vascular cellular adhesion molecule-1 (VCAM-1)/intercellular adhesion molecule-1 (ICAM-1). Fluorescent-activated cell sorting analysis showed that nicotine induced expression of functionally active VCAM-1/ICAM-1, since they increased leukocyte adherence to HCAECs. Oxygen free radicals, Rho A and nuclear factor kappaB (NF-kappaB) play a pivotal role in modulating these effects. Indeed, nicotine caused oxygen free radical production as well as activation of Rho A and NF-kappaB pathways, evaluated by malondialdehyde levels, pulldown assay and by electrophoretic mobility shift assay, respectively. Superoxide dimutase, Rho A (Y-27639) and NF-kappaB inhibitors (pyrrolidine dithiocarbamate ammonium, Bay 11-7082) suppressed nicotine effects on CAM expression. HMG-CoA reductase inhibitors prevented these nicotine-mediated effects by inhibiting free radical generation and by modulating activation of Rho A and NF-kappaB pathways.
Nicotine promotes CAM expression on HCAECs, shifting them toward a proatherosclerotic state. These effects might explain, at least in part, the deleterious cardiovascular consequences of cigarette smoking. HMG-CoA reductase inhibitors play an important role in preventing these phenomena.
吸烟易导致动脉粥样硬化及其并发症的发生。导致这些影响的机制尚未完全明确。我们研究了尼古丁是否可能在人冠状动脉内皮细胞（HCAECs）中促进动脉粥样硬化前期状态，并研究了3-羟基-3-甲基戊二酰辅酶A（HMG-CoA）还原酶抑制剂在预防这些现象中的作用。
实时聚合酶链反应显示，尼古丁可导致血管细胞黏附分子-1（VCAM-1）/细胞间黏附分子-1（ICAM-1）的信使核糖核酸水平呈剂量依赖性增加。荧光激活细胞分选分析显示，尼古丁可诱导功能性活性VCAM-1/ICAM-1的表达，因为它们增加了白细胞对HCAECs的黏附。氧自由基、Rho A和核因子κB（NF-κB）在调节这些作用中起关键作用。实际上，尼古丁分别通过丙二醛水平、下拉试验和电泳迁移率变动分析评估，导致了氧自由基的产生以及Rho A和NF-κB途径的激活。超氧化物歧化酶、Rho A（Y-27639）和NF-κB抑制剂（吡咯烷二硫代氨基甲酸铵、Bay 11-7082）可抑制尼古丁对细胞黏附分子表达的影响。HMG-CoA还原酶抑制剂通过抑制自由基生成以及调节Rho A和NF-κB途径的激活来预防这些尼古丁介导的作用。
尼古丁可促进HCAECs上细胞黏附分子的表达，使其向动脉粥样硬化前期状态转变。这些作用可能至少部分解释了吸烟对心血管的有害影响。HMG-CoA还原酶抑制剂在预防这些现象中起重要作用。
