Potential role of insulin receptor isoforms and IGF receptors in plaque instability of human and experimental atherosclerosis.
Potential role of insulin receptor isoforms and IGF receptors in plaque instability of human and experimental atherosclerosis.
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DOI：
10.1186/s12933-018-0675-2
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发表时间：
2018-02-20
影响因子：
9.3
通讯作者：
Benito M
中科院分区：
文献类型：
--
作者：
Beneit N;Martín-Ventura JL;Rubio-Longás C;Escribano Ó;García-Gómez G;Fernández S;Sesti G;Hribal ML;Egido J;Gómez-Hernández A;Benito M
与动脉粥样硬化斑块相关的临床并发症是由于斑块生长或不稳定导致破裂而引起的管腔阻塞。我们以前证明过表达胰岛素受体亚型A（伊拉）和胰岛素样生长因子-I受体（IGF-IR）赋予血管平滑肌细胞（VSMCs）增殖和迁移优势，促进动脉粥样硬化早期斑块生长。然而，胰岛素受体（IR）亚型，IGF-IR或胰岛素样生长因子-II受体（IGF-IIR）在晚期动脉粥样硬化过程中VSMCs凋亡中的作用仍不清楚。我们通过连续免疫沉淀胰岛素受体亚型B（IRB）和伊拉来评估IR亚型在人颈动脉粥样硬化斑块中的表达。Western blot分析测定人斑块中IGF-IR、IGF-IIR和α-平滑肌肌动蛋白（α-SMA）的表达。这些蛋白质的表达，以及凋亡细胞的存在，通过免疫组织化学分析在实验性动脉粥样硬化使用BATIRKO; ApoE−/−小鼠，一个模型显示更严重的血管损伤比ApoE−/−小鼠。最后，通过针对切割的半胱天冬酶3的蛋白质印迹评估了携带IR（IRLoxP+/+ VSMC）或不携带IR（IR−/− VSMC）、表达伊拉（伊拉VSMC）或表达IRB（IRB VSMC）的VSMC的凋亡。我们观察到与非复杂区域相比，在人类复杂斑块中伊拉/IRB比率显著降低。此外，复杂斑块显示IGF-IR表达减少，IGF-IIR表达增加，α-SMA水平降低，表明VSMC丢失。在实验性动脉粥样硬化中，我们发现24周龄BATIRKO; ApoE−/−小鼠主动脉中伊拉显著降低，IRB表达增加。此外，来自BATIRKO; ApoE−/−小鼠的动脉粥样硬化斑块具有更少的VSMC含量和更高数量的凋亡细胞。体外实验表明苦鬼臼脂素抑制IGF-IR可诱导VSMCs凋亡。与IRLoxP+/+ VSMCs相比，在表达较高IGF-IR水平的IR−/− VSMCs中，毒胡萝卜素诱导的凋亡较低。最后，IRB VSMCs比伊拉或IRLoxP+/+ VSMCs更容易发生毒胡萝卜素诱导的凋亡。在晚期人类动脉粥样硬化中，伊拉/IRB比率降低、IGF-IR表达降低或IGF-IIR增加可能有助于VSMCs凋亡，促进斑块不稳定性并增加斑块破裂及其临床后果的风险。本文的在线版本（10.1186/s12933-018-0675-2）包含补充材料，可供授权用户使用。
Clinical complications associated with atherosclerotic plaques arise from luminal obstruction due to plaque growth or destabilization leading to rupture. We previously demonstrated that overexpression of insulin receptor isoform A (IRA) and insulin-like growth factor-I receptor (IGF-IR) confers a proliferative and migratory advantage to vascular smooth muscle cells (VSMCs) promoting plaque growth in early stages of atherosclerosis. However, the role of insulin receptor (IR) isoforms, IGF-IR or insulin-like growth factor-II receptor (IGF-IIR) in VSMCs apoptosis during advanced atherosclerosis remains unclear. We evaluated IR isoforms expression in human carotid atherosclerotic plaques by consecutive immunoprecipitations of insulin receptor isoform B (IRB) and IRA. Western blot analysis was performed to measure IGF-IR, IGF-IIR, and α-smooth muscle actin (α-SMA) expression in human plaques. The expression of those proteins, as well as the presence of apoptotic cells, was analyzed by immunohistochemistry in experimental atherosclerosis using BATIRKO; ApoE−/− mice, a model showing more aggravated vascular damage than ApoE−/− mice. Finally, apoptosis of VSMCs bearing IR (IRLoxP+/+ VSMCs), or not (IR−/− VSMCs), expressing IRA (IRA VSMCs) or expressing IRB (IRB VSMCs), was assessed by Western blot against cleaved caspase 3. We observed a significant decrease of IRA/IRB ratio in human complicated plaques as compared to non-complicated regions. Moreover, complicated plaques showed a reduced IGF-IR expression, an increased IGF-IIR expression, and lower levels of α-SMA indicating a loss of VSMCs. In experimental atherosclerosis, we found a significant decrease of IRA with an increased IRB expression in aorta from 24-week-old BATIRKO; ApoE−/− mice. Furthermore, atherosclerotic plaques from BATIRKO; ApoE−/− mice had less VSMCs content and higher number of apoptotic cells. In vitro experiments showed that IGF-IR inhibition by picropodophyllin induced apoptosis in VSMCs. Apoptosis induced by thapsigargin was lower in IR−/− VSMCs expressing higher IGF-IR levels as compared to IRLoxP+/+ VSMCs. Finally, IRB VSMCs are more prone to thapsigargin-induced apoptosis than IRA or IRLoxP+/+ VSMCs. In advanced human atherosclerosis, a reduction of IRA/IRB ratio, decreased IGF-IR expression, or increased IGF-IIR may contribute to VSMCs apoptosis, promoting plaque instability and increasing the risk of plaque rupture and its clinical consequences. The online version of this article (10.1186/s12933-018-0675-2) contains supplementary material, which is available to authorized users.
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影响因子：
2.3
作者：
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