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Am J Physiol Heart Circ Physiol 281: H1946-H1954, 2001;
0363-6135/01 $5.00
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Vol. 281, Issue 5, H1946-H1954, November 2001

4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone, a nicotine derivative, induces apoptosis of endothelial cells

Patricia K. Tithof1, Mona Elgayyar1, Hildegard M. Schuller2, Maryann Barnhill2, and Richard Andrews3

1 Department of Comparative Medicine and 2 Department of Pathology, University of Tennessee College of Veterinary Medicine, and 3 Graduate School of Medicine, University of Tennessee, Knoxville, Tennessee 37996-4500

Smoking causes endothelial cell (EC) injury; however, neither the components of cigarette smoke nor the mechanisms responsible for this injury are understood. The nitrosated derivative of nicotine, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), has been implicated in the carcinogenic effects of tobacco; however, the effects of NNK on the cardiovascular system are largely unknown. NNK binds to beta 1- and beta 2-adrenergic receptors. Because beta -adrenergic receptor activation causes arachidonic acid (AA) release and cellular injury, we postulated that NNK causes EC injury by a mechanism that involves beta -adrenergic-mediated release of AA. NNK stimulated [3H]AA release from ECs, and this effect was mediated by both beta 1- and beta 2-adrenergic receptors because pretreatment with atenolol or ICI 118,551 inhibited the response. NNK also induced EC apoptosis, as measured by terminal deoxyribonucleotide transferase-mediated dUTP nick-end labeling and annexin V staining. NNK-mediated apoptosis was attenuated by pretreatment with atenolol or ICI 118,551. Furthermore, depletion of cellular AA by incubation with eicosapentaenoic acid abolished the apoptotic effect of NNK. These data suggest that NNK causes EC apoptosis by a mechanism that involves beta 1- and beta 2-adrenergic receptor-mediated release of AA.

endothelial cell; atherosclerosis; tobacco; nitrosamine


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