Chronic Nicotine Exposure Enhances Insulin-Induced Mitogenic Signaling via Up-Regulation of alpha 7 Nicotinic Receptors in Isolated Rat Aortic Smooth Muscle Cells

• Published in: Endocrinology (Philadelphia) 2007-02, Vol.148 (2), p.790-799
• Main Authors: Wada, Tsutomu, Naito, Maiko, Kenmochi, Hiroki, Tsuneki, Hiroshi, Sasaoka, Toshiyasu
• Format: Article
• Language: English
• ISSN: 0013-7227
• DOI: 10.1210/en.2006-0907

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 alpha 2-7, alpha 10, {szligbeta}1-3, 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- super(3)H]thymidine incorporation were effectively suppressed by a alpha 7-nAChR-selective antagonist, methyllycaconitine, and the phosphorylation of p44/42-MAPK was stimulated by a alpha 7-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 alpha 7-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 alpha 7-nAChR, which may be crucial for the development and progression of atherosclerosis in large vessels.