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.