Cigarette smoke-induced proinflammatory alterations in the endothelial phenotype: role of NAD(P)H oxidase activation.
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 microg/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)(*-) production. Dihydroethidine staining showed that increased O(2)(*-) generation was present both in endothelial and smooth muscle cells. CSE also increased vascular H(2)O(2) production (dichlorofluorescein fluorescence). Vascular mRNA expression of the proinflammatory cytokines IL-1beta, 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 H(2)O(2). In cultured endothelial cells, CSE elicited NF-kappaB 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 H(2)O(2) activates NF-kappaB, leading to proinflammatory alterations in vascular phenotype, which likely promotes development of atherosclerosis, especially if other risk factors are also present.
Orosz
Zsuzsanna
Z
Dept. of Physiology, New York Medical College, Valhalla, NY 10595, USA. zoltan_ungvari@nymc.edu
Csiszar
Anna
A
Labinskyy
Nazar
N
Smith
Kira
K
Kaminski
Pawel M
PM
Ferdinandy
Peter
P
Wolin
Michael S
MS
Rivera
Aracelie
A
Ungvari
Zoltan
Z
D000818:Animals; D001167:Arteritis / Q000201:enzymology* / Q000209:etiology*; D004730:Endothelium, Vascular / Q000187:drug effects / Q000201:enzymology*; D004789:Enzyme Activation / Q000187:drug effects; D008297:Male; D019255:NADPH Oxidases / Q000378:metabolism*; D010641:Phenotype; D051381:Rats; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000378:metabolism; D012907:Smoking / Q000009:adverse effects* / Q000378:metabolism*; D013638:Tars / Q000009:adverse effects*
D017382:Reactive Oxygen Species; D013638:Tars; C024746:tobacco tar; D019255:NADPH Oxidases