Chronic nicotine exposure enhances insulin-induced mitogenic signaling via up-regulation of alpha7 nicotinic receptors in isolated rat aortic smooth muscle cells.
Insulin resistance and smoking are significant risk factors for cardiac and cerebral vascular diseases. Because vascular smooth muscle cells play a key role in the development and progression of atherosclerosis, we investigated the effect of nicotine on insulin-induced mitogenic signaling in aortic vascular smooth muscle cells isolated from Sprague Dawley rats. RT-PCR revealed the expression of alpha2-7, alpha10, beta1-3, delta, and epsilon subunits of the nicotinic acetylcholine receptor (nAChR) in the cells. Short-term nicotine treatment stimulated phosphorylation of p44/42-MAPK, p38-MAPK, and signal transducer and activator of transcription 3. However, an additive effect of nicotine pretreatment on insulin stimulation was only observed on p44/42-MAPK. The nicotine-induced phosphorylation of p44/42-MAPK and [methyl-(3)H]thymidine incorporation were effectively suppressed by a alpha7-nAChR-selective antagonist, methyllycaconitine, and the phosphorylation of p44/42-MAPK was stimulated by a alpha7-nAChR-specific agonist, GTS21. Furthermore, the phosphorylation was mediated via calmodulin kinase II, Src, and Shc. Interestingly, long-term (48-h) pretreatment with nicotine increased the amount of alpha7-AChR in the plasma membrane and insulin-induced phosphorylation of p44/42-MAPK. These results provide the first evidence that acute exposure to nicotine enhances insulin-induced mitogenesis predominantly by affecting the phosphorylation of p44/42-MAPK and that chronic exposure further augments the insulin signal via up-regulation of alpha7-nAChR, which may be crucial for the development and progression of atherosclerosis in large vessels.
Wada
Tsutomu
T
Department of Clinical Pharmacology, University of Toyama, 2630 Sugitani, Toyama 930-0194, Japan.
Naito
Maiko
M
Kenmochi
Hiroki
H
Tsuneki
Hiroshi
H
Sasaoka
Toshiyasu
T
D000818:Animals; D001011:Aorta / Q000166:cytology / Q000378:metabolism*; D002478:Cells, Cultured; D004247:DNA / Q000096:biosynthesis; D004789:Enzyme Activation / Q000502:physiology; D006801:Humans; D007328:Insulin / Q000494:pharmacology*; D008297:Male; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D008938:Mitosis / Q000502:physiology*; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000378:metabolism*; D032389:Myocytes, Smooth Muscle / Q000378:metabolism; D009538:Nicotine / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011978:Receptors, Nicotinic / Q000378:metabolism*; D011994:Recombinant Proteins / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D015854:Up-Regulation / Q000502:physiology; D064569:alpha7 Nicotinic Acetylcholine Receptor
C579167:Chrna7 protein, human; C579165:Chrna7 protein, rat; D007328:Insulin; D011978:Receptors, Nicotinic; D011994:Recombinant Proteins; D064569:alpha7 Nicotinic Acetylcholine Receptor; D009538:Nicotine; D004247:DNA; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3