4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone, a nicotine derivative, induces apoptosis of endothelial cells.
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 beta1- and beta2-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 beta1- and beta2-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 beta1- and beta2-adrenergic receptor-mediated release of AA.
Tithof
P K
PK
Department of Comparative Medicine, University of Tennessee College of Veterinary Medicine, Knoxville, Tennessee 37996-4500, USA. ptithof@utk.edu
Elgayyar
M
M
Schuller
H M
HM
Barnhill
M
M
Andrews
R
R
D000818:Animals; D001011:Aorta / Q000166:cytology; D017209:Apoptosis / Q000187:drug effects*; D016718:Arachidonic Acid / Q000493:pharmacokinetics; D001161:Arteriosclerosis / Q000473:pathology; D002273:Carcinogens / Q000494:pharmacology*; D004730:Endothelium, Vascular / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D020287:In Situ Nick-End Labeling; D009538:Nicotine / Q000493:pharmacokinetics; D009602:Nitrosamines / Q000494:pharmacology*; D011943:Receptors, Adrenergic, beta / Q000378:metabolism; D012907:Smoking / Q000009:adverse effects; D013552:Swine; D014316:Tritium
D002273:Carcinogens; D009602:Nitrosamines; D011943:Receptors, Adrenergic, beta; D014316:Tritium; D016718:Arachidonic Acid; D009538:Nicotine; C016583:4-(N-methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone