Montelukast inhibits abdominal aortic aneurysm formation in mice via activating the AMPK/mTOR signalling pathway.

objectiveTo investigate the mechanism by which Montelukast inhibits abdominal aortic aneurysm (AAA) formation through the AMPK/mTOR signaling pathway in mice.

methodsMice 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.

resultsCompared 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.

conclusionMontelukast 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.