Chronic nicotine exposure enhances insulin-induced mitogenic signaling via up-regulation of alpha7 nicotinic receptors in isolated rat aortic smooth muscle cells.
Chronic nicotine exposure enhances insulin-induced mitogenic signaling via up-regulation of alpha7 nicotinic receptors in isolated rat aortic smooth muscle cells.
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DOI：
10.1210/en.2006-0907
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发表时间：
2007-02
期刊：
影响因子：
4.8
通讯作者：
T. Wada;M. Naito;H. Kenmochi;H. Tsuneki;T. Sasaoka
中科院分区：
文献类型：
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作者：
T. Wada;M. Naito;H. Kenmochi;H. Tsuneki;T. Sasaoka
胰岛素抵抗和吸烟是心脑血管疾病的重要危险因素。由于血管平滑肌细胞在动脉粥样硬化的发生和发展中起关键作用，我们研究了尼古丁对从Sprague道利大鼠分离的主动脉血管平滑肌细胞中胰岛素诱导的促有丝分裂信号传导的影响。RT-PCR显示细胞中烟碱乙酰胆碱受体（nAChR）的α 2 -7、α 10、β 1 -3、δ和δ亚基的表达。短期尼古丁处理刺激p44/42-MAPK，p38-MAPK和信号转导和转录激活因子3的磷酸化。然而，尼古丁预处理对胰岛素刺激的累加效应仅在p44/42-MAPK上观察到。α 7-nAChR选择性拮抗剂甲基可可碱可有效抑制烟碱诱导的p44/42-MAPK磷酸化和[甲基-（3）H]胸苷掺入，α 7-nAChR特异性激动剂GTS 21可刺激p44/42-MAPK磷酸化。此外，通过钙调蛋白激酶II，Src和Shc介导的磷酸化。有趣的是，长期（48小时）尼古丁预处理增加了质膜中α 7-AChR的量和胰岛素诱导的p44/42-MAPK磷酸化。这些结果提供了第一个证据，表明尼古丁急性暴露主要通过影响p44/42-MAPK的磷酸化来增强胰岛素诱导的有丝分裂，慢性暴露通过α 7-nAChR的上调进一步增强胰岛素信号，这可能对大血管中动脉粥样硬化的发展和进展至关重要。
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.