Mechanical stretch-induced endoplasmic reticulum stress, apoptosis and inflammation contribute to thoracic aortic aneurysm and dissection.
Mechanical stretch-induced endoplasmic reticulum stress, apoptosis and inflammation contribute to thoracic aortic aneurysm and dissection.
复制标题
DOI：
10.1002/path.4534
复制
发表时间：
2015-07
影响因子：
7.3
通讯作者：
Du, Jie
中科院分区：
文献类型：
--
作者：
Jia, Li-Xin;Zhang, Wen-Mei;Zhang, Hong-Jia;Li, Tao-Tao;Wang, Yue-Li;Qin, Yan-Wen;Gu, Hong;Du, Jie
胸主动脉瘤/夹层（TAAD）的特征是平滑肌细胞（SMC）过度丢失、细胞外基质（ECM）降解和炎症。响应于某些刺激，内质网（ER）应激被激活并调节细胞凋亡和炎症。过度凋亡促进主动脉炎症和变性，导致TAAD。因此，我们研究了ER应力在TAAD形成中的作用。给予赖氨酰氧化酶抑制剂富马酸3-氨基丙腈（BAPN）以诱导小鼠TAAD形成，其显示显著的SMC损失（α-SMA水平）。过量的细胞凋亡（TUNEL染色）和ER应激（ATF 4和CHOP）以及沿着炎症存在于来自小鼠和人的TAAD样品中。机械应力后SMC的转录谱显示了ER应激和炎症基因的表达。为了探索ER应激在引发退行性信号传导事件和TAAD中的因果作用，我们用BAPN处理野生型（CHOP +/+）或CHOP −/−小鼠，发现CHOP缺乏可防止TAAD形成和破裂，以及α-SMA水平降低。在CHOP −/−小鼠中，SMC凋亡和炎症均显著减少。此外，从CHOP −/−小鼠中分离的SMC对机械应力诱导的细胞凋亡具有抗性。总之，我们的结果表明，机械应力诱导的ER应力促进SMC凋亡，炎症和变性，为TAAD的形成和进展提供了见解。© 2015作者。病理学杂志由John Wiley & Sons Ltd代表大不列颠和爱尔兰病理学会出版。
Thoracic aortic aneurysm/dissection (TAAD) is characterized by excessive smooth muscle cell (SMC) loss, extracellular matrix (ECM) degradation and inflammation. In response to certain stimuli, endoplasmic reticulum (ER) stress is activated and regulates apoptosis and inflammation. Excessive apoptosis promotes aortic inflammation and degeneration, leading to TAAD. Therefore, we studied the role of ER stress in TAAD formation. A lysyl oxidase inhibitor, 3‐aminopropionitrile fumarate (BAPN), was administrated to induce TAAD formation in mice, which showed significant SMC loss (α‐SMA level). Excessive apoptosis (TUNEL staining) and ER stress (ATF4 and CHOP), along with inflammation, were present in TAAD samples from both mouse and human. Transcriptional profiling of SMCs after mechanical stress demonstrated the expression of genes for ER stress and inflammation. To explore the causal role of ER stress in initiating degenerative signalling events and TAAD, we treated wild‐type (CHOP +/+) or CHOP −/− mice with BAPN and found that CHOP deficiency protected against TAAD formation and rupture, as well as reduction in α‐SMA level. Both SMC apoptosis and inflammation were significantly reduced in CHOP −/− mice. Moreover, SMCs isolated from CHOP −/− mice were resistant to mechanical stress‐induced apoptosis. Taken together, our results demonstrated that mechanical stress‐induced ER stress promotes SMCs apoptosis, inflammation and degeneration, providing insight into TAAD formation and progression. © 2015 Authors. Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.
登录
查看更多内容
影响因子：
4.8
作者：
O'Neill, Christina M.;Lu, Christine;Nunemaker, Craig S.
通讯作者：
Nunemaker, Craig S.
DOI：
10.1152/ajpheart.01341.2008
发表时间：
2009-05-01
影响因子：
4.8
作者：
Leeper, Nicholas J.;Tedesco, Maureen M.;Quertermous, Thomas
通讯作者：
Quertermous, Thomas
DOI：
10.1073/pnas.94.3.849
发表时间：
1997-02-04
影响因子：
11.1
作者：
Maniotis, AJ;Chen, CS;Ingber, DE
通讯作者：
Ingber, DE
影响因子：
4
作者：
Asano, Yoshiya;Koishi, Kyoko;McLennan, Ian S.
通讯作者：
McLennan, Ian S.
影响因子：
14.8
作者：
Golovina, Vera A.;Blaustein, Mordecai P.
通讯作者：
Blaustein, Mordecai P.