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Cigarette smoke-induced proinflammatory alterations in the endothelial phenotype: role of NAD(P)H oxidase activation

¹Department of Physiology, New York Medical College, Valhalla, New York; and ²Cardiovascular Research Group, Department of Biochemistry, University of Szeged, Szeged, Hungary

Submitted 7 June 2006 ; accepted in final form 13 September 2006

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 µg/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 O₂^– production. Dihydroethidine staining showed that increased O₂^– 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, IL-6, and TNF- 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-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-B, leading to proinflammatory alterations in vascular phenotype, which likely promotes development of atherosclerosis, especially if other risk factors are also present.

tobacco; oxidative stress; stroke; plaque development; cytokine; arteriosclerosis; endothelial dysfunction

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