Tauroursodeoxycholic Acid Attenuates Angiotensin II Induced Abdominal Aortic Aneurysm Formation in Apolipoprotein E-deficient Mice by Inhibiting Endoplasmic Reticulum Stress
Tauroursodeoxycholic Acid Attenuates Angiotensin II Induced Abdominal Aortic Aneurysm Formation in Apolipoprotein E-deficient Mice by Inhibiting Endoplasmic Reticulum Stress
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牛磺熊去氧胆酸通过抑制内质网应激减轻载脂蛋白 E 缺陷小鼠中血管紧张素 II 诱导的腹主动脉瘤形成
DOI：
10.1016/j.ejvs.2016.10.026
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发表时间：
2017
影响因子：
5.7
通讯作者：
Wei Y.
中科院分区：
文献类型：
--
作者：
Qin Y.;Wang Y.;Liu O.;Jia L.;Fang W.;Du J.;Wei Y.
目的腹主动脉瘤（AAA）是一种以平滑肌细胞（SMC）凋亡、炎性细胞浸润、新生血管形成和细胞外基质降解为特征的疾病。先前的工作表明，内质网（ER）应激和SMC凋亡增加，在小鼠模型和人胸主动脉瘤。然而，是否ER应力激活AAA的形成，是否抑制ER应力衰减AAA是unknow.MethodsHuman AAA和对照组主动脉标本收集。免疫组化法检测ER应激分子伴侣葡萄糖调节蛋白（GRP）-78和GRP-94的表达。研究了ER应激抑制剂牛磺熊去氧胆酸（TUDCA）对血管紧张素（Ang）II诱导的载脂蛋白E−/−小鼠AAA形成的影响。弹性蛋白染色观察弹性断裂。免疫组化和Western blot分析，检测ER应激分子和凋亡分子的蛋白表达。结果人AAA和Ang II诱导的ApoE−/−小鼠垂体瘤区GRP-78和GRP-94表达显著上调（p< .05）。TUDCA显著减弱了Ang II诱导的ApoE−/−小鼠的腹部肿块最大直径（p<0.05）。TUDCA显著降低ER应激分子伴侣的表达和凋亡细胞数（p<0.05）。此外，TUDCA显著降低Ang II诱导的ApoE−/−小鼠中caspase-3、caspase-12、C/EBP同源蛋白、c-Jun N-末端激酶激活转录因子4、X-box结合蛋白和真核细胞起始因子2α等凋亡分子的表达（p< .05）。TUDCA通过抑制ER应激介导的细胞凋亡减弱ApoE−/−小鼠中Ang II诱导的AAA形成
Objective/BackgroundAbdominal aortic aneurysm (AAA) is characterised by the infiltration of smooth muscle cell (SMC) apoptosis, inflammatory cells, neovascularisation, and degradation of the extracellular matrix. Previous work has shown that endoplasmic reticulum (ER) stress and SMC apoptosis were increased both in a mouse model and human thoracic aortic aneurysm. However, whether the ER stress is activated in AAA formation and whether suppressing ER stress attenuates AAA is unknown.MethodsHuman AAA and control aorta samples were collected. Expression of ER stress chaperones glucose-regulated protein (GRP)-78 and GRP-94 was detected by immunohistochemical staining. The effect of ER stress inhibitor tauroursodeoxycholic acid (TUDCA) on AAA formation in angiotensin (Ang) II induced apolipoprotein E−/−mice was explored. Elastin staining was used to observe the rupture of elastic fragmentation. Immunohistochemistry and Western blot analysis were performed, to detect the protein expression of ER stress chaperones and apoptosis molecules.ResultsThere was significant upregulation of GRP-78 and GRP-94 in aneurysmal areas of human AAA and Ang II induced ApoE−/−mice (p< .05). TUDCA significantly attenuated the maximum diameters of abdominal aortas in Ang II induced ApoE−/−mice (p< .05). TUDCA significantly reduced expression of ER stress chaperones and the apoptotic cell numbers (p< .05). Furthermore, TUDCA significantly reduced expression of apoptosis molecules, such as caspase-3, caspase-12, C/EBP homologous protein, c-Jun N-terminal kinase activating transcription factor 4, X-box binding protein, and eukaryotic initiation factor 2α in Ang II induced ApoE−/−mice (p< .05).ConclusionThe results suggest that ER stress is involved in human and Ang II induced AAA formation in ApoE−/−mice. TUDCA attenuates Ang II induced AAA formation in ApoE−/−mice by inhibiting ER stress mediated apoptosis.