Huang Jian, Zhuang Jiawei, Wang Jiamao, Shan Zhonggui
The First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, 361000, China.
Langenbecks Arch Surg. 2024 Nov 27;409(1):362. doi: 10.1007/s00423-024-03527-1.
To investigate the mechanism by which Montelukast inhibits abdominal aortic aneurysm (AAA) formation through the AMPK/mTOR signaling pathway in mice.
Mice were randomly assigned to the Normal group, Model group, Montelukast group, and Montelukast + compound C (C.C) group. The Model, Montelukast, and Montelukast + C.C groups were induced with AAA by continuous infusion of 1000 ng/kg/min of Ang II. The Montelukast group received daily oral administration of 10 mg/kg Montelukast, while the Montelukast + C.C group received 10 mg/kg Montelukast and 10 mg/kg C.C orally for 28 days. Abdominal aortas were isolated, and their diameters and AAA occurrence were measured using a micrometer. Histological analysis was performed using Hematoxylin-Eosin (HE) staining to assess the morphological changes. TUNEL staining was conducted to measure cell apoptosis levels in the abdominal aortas. Western Blot was employed to evaluate protein expressions of Bax, Bcl-2, MMP-2, MMP-9, α1-AT, p-AMPK, AMPK, p-mTOR, mTOR in the abdominal aortic tissues. qRT-PCR was used to assess the expression of IL-6, TNF-α, IFN-γ in the mouse abdominal aortas.
Compared to the Normal group, the Model group showed significantly increased abdominal aortic diameter, AAA occurrence, TUNEL positivity, Bax/Bcl-2 ratio, IL-6, TNF-α, IFN-γ, MMP-2, MMP-9, p-mTOR/mTOR, and decreased α1-AT, p-AMPK/AMPK (P < 0.05). The Montelukast group exhibited significant decreases in abdominal aortic diameter, AAA occurrence, TUNEL positivity, Bax/Bcl-2 ratio, IL-6, TNF-α, IFN-γ, MMP-2, MMP-9, p-mTOR/mTOR, and increases in α1-AT, p-AMPK/AMPK compared to the Model group (P < 0.05). The Montelukast + C.C group showed opposite trends compared to the Montelukast group (P < 0.05). The Normal group exhibited intact abdominal aortic wall structure with orderly arranged cells. The Model group showed thickened aortic walls, plaque formation, and inflammatory cell infiltration. The Montelukast group demonstrated reduced aortic wall thickening, approaching a morphology closer to the Normal group. The Montelukast + C.C group exhibited a morphology between the Model and Montelukast groups.
Montelukast can inhibit AAA formation in mice, possibly through the downregulation of cell apoptosis, inflammatory response, and matrix metalloproteinase levels via the AMPK/mTOR signaling pathway.
研究孟鲁司特通过小鼠体内的AMPK/mTOR信号通路抑制腹主动脉瘤（AAA）形成的机制。
将小鼠随机分为正常组、模型组、孟鲁司特组和孟鲁司特+复合C（C.C）组。模型组、孟鲁司特组和孟鲁司特+C.C组通过持续输注1000 ng/kg/min的血管紧张素II（Ang II）诱导形成AAA。孟鲁司特组每日口服10 mg/kg孟鲁司特，而孟鲁司特+C.C组每日口服10 mg/kg孟鲁司特和10 mg/kg C.C，持续28天。分离腹主动脉，用千分尺测量其直径和AAA发生率。采用苏木精-伊红（HE）染色进行组织学分析，以评估形态学变化。进行TUNEL染色以测量腹主动脉中的细胞凋亡水平。采用蛋白质免疫印迹法评估腹主动脉组织中Bax、Bcl-2、基质金属蛋白酶-2（MMP-2）、基质金属蛋白酶-9（MMP-9）、α1-抗胰蛋白酶（α1-AT）、磷酸化腺苷酸活化蛋白激酶（p-AMPK）、腺苷酸活化蛋白激酶（AMPK）、磷酸化哺乳动物雷帕霉素靶蛋白（p-mTOR）、哺乳动物雷帕霉素靶蛋白（mTOR）的蛋白表达。采用实时荧光定量聚合酶链反应（qRT-PCR）评估小鼠腹主动脉中白细胞介素-6（IL-6）、肿瘤坏死因子-α（TNF-α）、干扰素-γ（IFN-γ）的表达。
与正常组相比，模型组腹主动脉直径、AAA发生率、TUNEL阳性率、Bax/Bcl-2比值、IL-6、TNF-α、IFN-γ、MMP-2、MMP-9、p-mTOR/mTOR显著升高，α1-AT、p-AMPK/AMPK降低（P<0.05）。与模型组相比，孟鲁司特组腹主动脉直径、AAA发生率、TUNEL阳性率、Bax/Bcl-2比值、IL-6、TNF-α、IFN-γ、MMP-2、MMP-9、p-mTOR/mTOR显著降低，α1-AT、p-AMPK/AMPK升高（P<0.05）。与孟鲁司特组相比，孟鲁司特+C.C组呈现相反趋势（P<0.05）。正常组腹主动脉壁结构完整，细胞排列有序。模型组主动脉壁增厚，有斑块形成和炎性细胞浸润。孟鲁司特组主动脉壁增厚减轻，形态更接近正常组。孟鲁司特+C.C组的形态介于模型组和孟鲁司特组之间。
孟鲁司特可抑制小鼠AAA的形成，可能是通过AMPK/mTOR信号通路下调细胞凋亡、炎症反应和基质金属蛋白酶水平实现的。
