Down-regulating effect of nicotine on connexin43 gap junctions in human umbilical vein endothelial cells is attenuated by statins.
We investigated the effect of nicotine on connexin43 (Cx43) expression and gap-junctional communication in human umbilical vein endothelial cells (HUVEC). We also evaluated whether the effect requires activation of acetyl choline receptors sensitive to nicotine (nAChRs) and is altered by statins. The results showed that expression of Cx43 protein is reduced by nicotine in a dose-dependent manner (6 x 10(-4) M nicotine vs control, 33% reduction, p < 0.01), though Cx43 mRNA is up-regulated (6 x 10(-4) M nicotine vs control, 36% increase, p < 0.01). Concomitantly, the communication function, determined by fluorescence recovery after photobleaching, is decreased (6 x 10(-4) M nicotine vs control, 38% reduction, p < 0.05). Such a down-regulation of Cx43 gap junctions by nicotine disappears in the presence of the nAChRs antagonist, dihydro-beta-erythroidine, and protease inhibitors leupeptin plus N-acetyl-Leu-Leu-Norleu-al (ALLN). Similarly, the effect of nicotine is attenuated by statins, including fluvastatin, lovastatin, pravastatin, and simvastatin, even at the presence of mevalonate. We concluded that i) nicotine down-regulates Cx43 expression and gap-junctional communication in HUVEC via post-transcriptional modification, which involves enhancement of Cx43 proteolysis; ii) the effect of nicotine is mediated via activation of nAChRs; and iii) the effect of nicotine is attenuated by statins through mechanisms outside the hypolipidemic pathway.
Tsai
Cheng-Ho
CH
Department of Internal Medicine, Mackay Memorial Hospital, Mackay Junior College of Nursing, Taipei Medical University, Taipei, Taiwan.
Yeh
Hung-I
HI
Tian
Tin-Yi
TY
Lee
Yi-Nan
YN
Lu
Chi-Sheng
CS
Ko
Yu-Shien
YS
D002478:Cells, Cultured; D018031:Connexin 43 / Q000235:genetics / Q000378:metabolism*; D015536:Down-Regulation / Q000187:drug effects*; D004730:Endothelium, Vascular / Q000378:metabolism* / Q000648:ultrastructure; D017629:Gap Junctions / Q000187:drug effects* / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D008798:Mevalonic Acid / Q000494:pharmacology; D009538:Nicotine / Q000494:pharmacology*; D018733:Nicotinic Antagonists / Q000494:pharmacology; D038761:Photobleaching; D011480:Protease Inhibitors / Q000494:pharmacology; D012333:RNA, Messenger; D011978:Receptors, Nicotinic / Q000378:metabolism; D014471:Umbilical Veins / Q000166:cytology / Q000378:metabolism*
D018031:Connexin 43; D018733:Nicotinic Antagonists; D011480:Protease Inhibitors; D012333:RNA, Messenger; D011978:Receptors, Nicotinic; D009538:Nicotine; D008798:Mevalonic Acid