Insulin promotes vascular smooth muscle cell proliferation and apoptosis via differential regulation of tumor necrosis factor-related apoptosis-inducing ligand
Insulin promotes vascular smooth muscle cell proliferation and apoptosis via differential regulation of tumor necrosis factor-related apoptosis-inducing ligand
复制标题
DOI：
10.1111/1753-0407.12339
复制
发表时间：
2016-07-01
影响因子：
4.5
通讯作者：
Kavurma, Mary M.
中科院分区：
文献类型：
--
作者：
Harith, Hanis H.;Di Bartolo, Belinda A.;Kavurma, Mary M.
背景胰岛素调节葡萄糖稳态，但也可促进血管平滑肌（VSMC）增殖，在动脉粥样硬化形成中起重要作用。最近，我们发现肿瘤坏死因子相关凋亡诱导配体（TRAIL）通过加速血管平滑肌细胞的生长刺激内膜增厚。本研究的目的是确定是否胰岛素诱导的VSMCs的影响发生通过TRAIL.MethodsExpression的TRAIL和TRAIL受体在胰岛素和葡萄糖的反应，通过聚合酶链反应测定。使用野生型和位点特异性突变的TRAIL启动子的转录活性进行了评估。进行染色质免疫沉淀研究。VSMC增殖和凋亡的measurement.ResultsInsulin和葡萄糖暴露于VSMC 24小时刺激TRAIL mRNA的表达。这在转录水平上也很明显。胰岛素和葡萄糖诱导的TRAIL转录活性被显性负特异性蛋白-1（Sp1）过表达阻断。在TRAIL启动子上有5个功能性的Sp1结合元件（Sp1-1、Sp1-2、Sp 5/6和Sp1-7）。胰岛素需要Sp1-1和Sp1-2位点，但葡萄糖需要所有Sp1结合位点来诱导转录。此外，胰岛素（而不是葡萄糖）能够促进VSMC增殖随着时间的推移，与诱饵受体-2（DcR 2）的表达增加。与此相反，慢性5天暴露于1 μ g/mL胰岛素抑制TRAIL和DcR 2的表达，并减少了TRAIL启动子上的Sp1富集。这与增加的细胞death.ConclusionsThe本研究的结果提供了一个新的机制如何TRAIL是由胰岛素调节的见解。这可能对糖尿病相关心血管疾病的不同阶段具有重要意义。因此，TRAIL可以提供一种新的治疗方案，以打击胰岛素诱导的血管病变。
BackgroundInsulin regulates glucose homeostasis but can also promote vascular smooth muscle (VSMC) proliferation, important in atherogenesis. Recently, we showed that tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) stimulates intimal thickening via accelerated growth of VSMCs. The aim of the present study was to determine whether insulin-induced effects on VSMCs occur via TRAIL.MethodsExpression of TRAIL and TRAIL receptor in response to insulin and glucose was determined by polymerase chain reaction. Transcriptional activity was assessed using wild-type and site-specific mutations of the TRAIL promoter. Chromatin immunoprecipitation studies were performed. VSMC proliferation and apoptosis was measured.ResultsInsulin and glucose exposure to VSMC for 24h stimulated TRAIL mRNA expression. This was also evident at the transcriptional level. Both insulin- and glucose-inducible TRAIL transcriptional activity was blocked by dominant-negative specificity protein-1 (Sp1) overexpression. There are five functional Sp1-binding elements (Sp1-1, Sp1-2, Sp-5/6 and Sp1-7) on the TRAIL promoter. Insulin required the Sp1-1 and Sp1-2 sites, but glucose needed all Sp1-binding sites to induce transcription. Furthermore, insulin (but not glucose) was able to promote VSMC proliferation over time, associated with increased decoy receptor-2 (DcR2) expression. In contrast, chronic 5-day exposure of VSMC to 1 mu g/mL insulin repressed TRAIL and DcR2 expression, and reduced Sp1 enrichment on the TRAIL promoter. This was associated with increased cell death.ConclusionsThe findings of the present study provide a new mechanistic insight into how TRAIL is regulated by insulin. This may have significant implications at different stages of diabetes-associated cardiovascular disease. Thus, TRAIL may offer a novel therapeutic solution to combat insulin-induced vascular pathologies.