Implication of Insulin Receptor A Isoform and IRA/IGF-IR Hybrid Receptors in the Aortic Vascular Smooth Muscle Cell Proliferation: Role of TNF-α and IGF-II
Implication of Insulin Receptor A Isoform and IRA/IGF-IR Hybrid Receptors in the Aortic Vascular Smooth Muscle Cell Proliferation: Role of TNF-α and IGF-II
复制标题
DOI：
10.1210/en.2012-2161
复制
发表时间：
2013-07-01
期刊：
影响因子：
4.8
通讯作者：
Benito, Manuel
中科院分区：
文献类型：
--
作者：
Gomez-Hernandez, Almudena;Escribano, Oscar;Benito, Manuel
为了评估胰岛素受体（IR）亚型（伊拉和IRB）在动脉粥样硬化过程中涉及的血管平滑肌细胞（VSMC）增殖中的作用，我们产生了携带IR（野生型VSMC; IRLoxP（+/+）VSMC）、缺乏IR（IR-/-VSMC）或表达伊拉（伊拉VSMC）或IRB（IRB VSMC）的新VSMC系。胰岛素和不同的致动脉粥样硬化刺激诱导IRLoxP（+/+）VSMCs伊拉表达显著增加。此外，胰岛素，通过ERK信号，和促动脉粥样硬化刺激，通过ERK和p38信号，诱导伊拉比IRB VSMCs更高的增殖。后一种效应可能是由于伊拉细胞显示出血管紧张素II、内皮素1和血栓素2受体的较高表达以及伊拉与这些受体之间的基础关联。此外，TNF-α以配体依赖性方式诱导伊拉和TNF-α受体1（TNF-R1）之间的更高关联。另一方面，伊拉过表达可能有利于IGF-II的致动脉粥样硬化作用。因此，IGF-II或TNF-α诱导伊拉和IGF-I受体（IGF-IR）过表达以及VSMC中伊拉/IGF-IR杂合受体的增加。更重要的是，我们在ApoE（-/-）和BATIRKO小鼠（2种显示血管损伤的模型）的主动脉中观察到伊拉、TNF-R1和IGF-IR表达的显著增加以及伊拉与TNF-R1或IGF-IR的更高相关性。此外，抗TNF-α治疗防止了BATIRKO小鼠的这些作用。最后，我们的数据表明，伊拉亚型及其与TNF-R1或IGF-IR的关联赋予VSMCs增殖优势，主要是响应于TNF-α或IGF-II，这可能在早期动脉粥样硬化过程中具有重要意义。（内分泌学154：2352-2364，2013）
To assess the role of insulin receptor (IR) isoforms (IRA and IRB) in the proliferation of vascular smooth muscle cells (VSMCs) involved in the atherosclerotic process, we generated new VSMC lines bearing IR (wild-type VSMCs; IRLoxP(+/+) VSMCs), lacking IR (IR-/- VSMCs) or expressing IRA (IRA VSMCs) or IRB (IRB VSMCs). Insulin and different proatherogenic stimuli induced a significant increase of IRA expression in IRLoxP(+/+) VSMCs. Moreover, insulin, through ERK signaling, and the proatherogenic stimuli, through ERK and p38 signaling, induced a higher proliferation in IRA than IRB VSMCs. The latter effect might be due to IRA cells showing a higher expression of angiotensin II, endothelin 1, and thromboxane 2 receptors and basal association between IRA and these receptors. Furthermore, TNF-alpha induced in a ligand-dependent manner a higher association between IRA and TNF-alpha receptor 1 (TNF-R1). On the other hand, IRA overexpression might favor the atherogenic actions of IGF-II. Thereby, IGF-II or TNF-alpha induced IRA and IGF-I receptor (IGF-IR) overexpression as well as an increase of IRA/IGF-IR hybrid receptors in VSMCs. More importantly, we observed a significant increase of IRA, TNF-R1, and IGF-IR expression as well as higher association of IRA with TNF-R1 or IGF-IR in the aorta from ApoE(-/-) and BATIRKO mice, 2 models showing vascular damage. In addition, anti-TNF-alpha treatment prevented those effects in BATIRKO mice. Finally, our data suggest that the IRA isoform and its association with TNF-R1 or IGF-IR confers proliferative advantage to VSMCs, mainly in response to TNF-alpha or IGF-II, which might be of significance in the early atherosclerotic process. (Endocrinology 154: 2352-2364, 2013)