内质网应激介导激活的C/EBP同源蛋白(CHOP)在腹主动脉瘤发病中的作用及机制研究

Abdominal aortic aneurysm (AAA) is an aortic disease with high mortality rate after rupture. Studies indicated that AAA is closely related with abdominal aortic smooth muscle cells (SMC) apoptosis and inflammation. Previous studies have documented endoplasmic reticulum (ER) stress participates in the pathogenesis of atherosclerosis, heart failure and other cardiovascular diseases by activating C/EBP homologous protein (CHOP) - mediated apoptosis and inflammation. However, whether there's a link between AAA and ER stress has yet not been documented. In preliminary studies, we found that the ER stress and its downstream CHOP were strongly activated in AAA patients' aortic tissues compared with normal aortic tissues, suggesting that ER stress and CHOP may be involved in the pathogenesis of AAA. We therefore hypothesized that endoplasmic reticulum stress participates in the progression of AAA via activation its downstream effector proteins CHOP. The underlying mechanisms involved are likely via CHOP-mediated apoptosis and inflammatory pathways to induce SMC apoptosis and tissue inflammation. To prove this hypothesis, this study will utilize human samples and CHOP-/ - mice, to investigate the role and the mechanisms of ER stress and CHOP in AAA pathogenesis in the level of human, animals, and cells, and to provide a new target for AAA prevention and treatment.

腹主动脉瘤（AAA）是一种以腹主动脉局限性扩张为特征的血管性疾病，受累血管破裂后死亡率极高。AAA的发病机制尚未完全明确，可能与腹主动脉平滑肌细胞（SMC）凋亡以及炎症反应密切相关。内质网应激通过激活C/EBP同源蛋白（CHOP），介导细胞凋亡及炎症反应，与多种心血管疾病的发生发展密切相关，然而，目前尚未见有内质网应激与AAA关系的报道。我们前期研究发现AAA患者受累血管组织中内质网应激标志蛋白以及其下游效应蛋白CHOP的表达明显升高，提示内质网应激及CHOP可能参与AAA的病理生理过程。从而推测，内质网应激可能通过激活下游效应蛋白CHOP，后者介导的凋亡及炎症反应通路，诱发SMC凋亡和组织炎症反应，从而参与AAA的发生发展。为证明这一假说，本实验利用人体标本及CHOP-/-小鼠，在人体、动物、细胞三个层面，研究内质网应激与CHOP在AAA发病中的作用及机制,从而为AAA的防治提供新思路。

腹主动脉瘤（AAA）是一种以腹主动脉局限性扩张为特征的主动脉疾病，受累血管破裂后死亡率极高。AAA 的发病机制尚未完全明确，可能与腹主动脉平滑肌细胞（SMC）凋亡以及炎症反应密切相关。内质网应激通过激活 C/EBP 同源蛋白（CHOP），介导细胞凋亡及炎症反应，参与多种心血管疾病的发生发展，然而，目前尚未见有内质网应激与 AAA关系的报道。我们前期研究发现 AAA 患者受累血管组织中内质网应激标志蛋白以及其下游效应蛋白 CHOP 的表达明显升高，提示内质网应激及 CHOP 可能参与 AAA 的病理生理过程。从而推测，内质网应激可能通过激活下游效应蛋白 CHOP，后者介导的凋亡及炎症反应通路，诱发SMC 凋亡和组织炎症反应，从而参与 AAA 的发生发展。为证明这一假说，本项目利用人体标本及 CHOP-/-小鼠，在人体、动物、细胞三个层面，明确了内质网应激与 CHOP 在 AAA 发病中的作用及机制，从而为 AAA 的防治提供新思路。

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