Guo Jingjing, Wang Zhu, Xue Ming, Mi Lei, Zhao Mengpeng, Ma Chao, Wu Jian, Han Xinqiang
Department of Obstetrics and Gynecology, Binzhou Medical University Hospital, China.
Department of Interventional Medicine and Vascular Surgery, Binzhou Medical University Hospital, China.
Adv Clin Exp Med. 2022 Jan;31(1):59-69. doi: 10.17219/acem/142026.
Abdominal aortic aneurysm (AAA) is a pathological dilation of the abdominal aorta. It is often asymptomatic, yet it has a high susceptibility to rupture. Our previous study showed that metformin protected against the pathophysiology of AAA by reducing the activation of the PI3K/AKT/mTOR pathway.
To investigate the potential involvement of the autophagy-related pathways in AAA and the ability of metformin to modulate these effects.
The expression of autophagy-related proteins was detected with western blot in patients with AAA. Angiotensin II (Ang-II) was also used to construct an AAA model in mice and in vascular smooth muscle cells (VSMCs). The expression of Atg7 and Atg4 was determined using western blot assay. The Atg7 expression was regulated by overexpressed plasmid, siRNA (small interfering RNA), or metformin, and cell proliferation, migration, apoptosis and autophagy caused by Ang-II were examined.
Autophagy-related proteins were increased in patients with AAA. The Ang-II also induced the expression of Atg7, and metformin reversed this effect both in vivo and in vitro. The suppression of Atg7 inhibited cell proliferation and cell migration, and reduced cell apoptosis and autophagy, while the overexpression of Atg7 enhanced cell proliferation and migration, and induced cell apoptosis and autophagy. Furthermore, Atg7 regulated the expression of the autophagy-related protein in Ang-II treated VSMCs. The Atg7-mediated autophagy was also attenuated by metformin.
Metformin reduced autophagy in AAA and this effect was mediated by Atg7, suggesting that Atg7 is a potential downstream effector of metformin in protecting against the pathophysiology of AAA.
腹主动脉瘤（AAA）是腹主动脉的病理性扩张。它通常无症状，但破裂风险高。我们之前的研究表明，二甲双胍通过降低PI3K/AKT/mTOR通路的激活来预防AAA的病理生理过程。
研究自噬相关通路在AAA中的潜在作用以及二甲双胍调节这些作用的能力。
采用蛋白质免疫印迹法检测AAA患者自噬相关蛋白的表达。还使用血管紧张素II（Ang-II）在小鼠和血管平滑肌细胞（VSMC）中构建AAA模型。采用蛋白质免疫印迹法测定Atg7和Atg4的表达。通过过表达质粒、小干扰RNA（siRNA）或二甲双胍调节Atg7的表达，并检测Ang-II引起的细胞增殖、迁移、凋亡和自噬。
AAA患者自噬相关蛋白增加。Ang-II也诱导Atg7的表达，二甲双胍在体内和体外均能逆转这种作用。抑制Atg7可抑制细胞增殖和迁移，减少细胞凋亡和自噬，而过表达Atg7则增强细胞增殖和迁移，诱导细胞凋亡和自噬。此外，Atg7调节Ang-II处理的VSMC中自噬相关蛋白的表达。二甲双胍也减弱了Atg7介导的自噬。
二甲双胍可降低AAA中的自噬，且这种作用由Atg7介导，提示Atg7是二甲双胍预防AAA病理生理过程的潜在下游效应分子。
