Wu Jenny C F, Chruscinski Andrzej, De Jesus Perez Vinicio A, Singh Harvir, Pitsiouni Maria, Rabinovitch Marlene, Utz Paul J, Cooke John P
Department of Cardiovascular Medicine, Stanford University, Stanford, California 94305, USA.
J Cell Biochem. 2009 Oct 1;108(2):433-46. doi: 10.1002/jcb.22270.
Pathological angiogenesis contributes to tobacco-related diseases such as malignancy, atherosclerosis and age-related macular degeneration. Nicotine acts on endothelial nicotinic acetylcholine receptors (nAChRs) to activate endothelial cells and to augment pathological angiogenesis. In the current study, we studied nAChR subunits involved in these actions. We detected mRNA for all mammalian nAChR subunits except alpha(2), alpha(4), gamma, and delta in four different types of ECs. Using siRNA methodology, we found that the alpha(7) nAChR plays a dominant role in nicotine-induced cell signaling (assessed by intracellular calcium and NO imaging, and studies of protein expression and phosphorylation), as well as nicotine-activated EC functions (proliferation, survival, migration, and tube formation). The alpha(9) and alpha(7) nAChRs have opposing effects on nicotine-induced cell proliferation and survival. Our studies reveal a critical role for the alpha(7) nAChR in mediating the effects of nicotine on the endothelium. Other subunits play a modulatory role. These findings may have therapeutic implications for diseases characterized by pathological angiogenesis.
病理性血管生成与烟草相关疾病有关，如恶性肿瘤、动脉粥样硬化和年龄相关性黄斑变性。尼古丁作用于内皮细胞烟碱型乙酰胆碱受体（nAChRs），激活内皮细胞并增强病理性血管生成。在本研究中，我们研究了参与这些作用的nAChR亚基。我们在四种不同类型的内皮细胞中检测到了除α(2)、α(4)、γ和δ之外的所有哺乳动物nAChR亚基的mRNA。使用小干扰RNA（siRNA）方法，我们发现α(7) nAChR在尼古丁诱导的细胞信号传导（通过细胞内钙和一氧化氮成像以及蛋白质表达和磷酸化研究进行评估）以及尼古丁激活的内皮细胞功能（增殖、存活、迁移和管腔形成）中起主导作用。α(9)和α(7) nAChRs对尼古丁诱导的细胞增殖和存活具有相反的作用。我们的研究揭示了α(7) nAChR在介导尼古丁对内皮细胞的作用中起关键作用。其他亚基起调节作用。这些发现可能对以病理性血管生成为特征的疾病具有治疗意义。
