Montelukast, a Cysteinyl Leukotriene Receptor 1 Antagonist, Induces M2 Macrophage Polarization and Inhibits Murine Aortic Aneurysm Formation

• Published in: BioMed research international Vol. 2019; no. 2019; pp. 1 - 11
• Main Authors: Usui, Akihiko, Yamawaki-Ogata, Aika, Narita, Yuji, Kawai, Yohei, Komori, Kimihiro
• Format: Journal Article
• Language: English
• Published: Cairo, Egypt Hindawi Publishing Corporation 01.01.2019; Hindawi; John Wiley & Sons, Inc; Hindawi Limited
• Subjects: Abdomen; Acetates - pharmacology; Acetates - therapeutic use; Analysis; Aneurysms; Angiotensin; Angiotensin II; Animals; Aorta - drug effects; Aorta - enzymology; Aorta - pathology; Aortic Aneurysm - diagnostic imaging; Aortic Aneurysm - drug therapy; Aortic Aneurysm - pathology; Aortic aneurysms; Apolipoprotein E; Arginase; Arginase - genetics; Arginase - metabolism; Arteriosclerosis; Asthma; Atherosclerosis; Cell Line; Cell Polarity - drug effects; Cell surface; Chemokines - metabolism; Coronary vessels; Cyclopropanes; Cytokines; Enzyme-linked immunosorbent assay; Ethylenediaminetetraacetic acid; Extracellular matrix; Flow cytometry; Fluorescence; Gelatinase A; Gelatinase B; Gene expression; Gene Expression Regulation - drug effects; IL-1β; Induced infiltration; Infiltration; Inflammation; Inflammation Mediators - metabolism; Intercellular Signaling Peptides and Proteins - metabolism; Interleukin 10; Interleukin-10 - genetics; Interleukin-10 - metabolism; Interleukins; Laboratory animals; Macrophages; Macrophages - drug effects; Macrophages - metabolism; Matrix metalloproteinase; Matrix Metalloproteinase 2 - metabolism; Matrix Metalloproteinase 9 - metabolism; Matrix metalloproteinases; Metal concentrations; Metal industry; Mice, Inbred C57BL; Monocytes; Montelukast; Pathogenesis; Polarization; Polymerase chain reaction; Proteins; Quinolines - pharmacology; Quinolines - therapeutic use; Receptors, Leukotriene - metabolism; Scientific equipment and supplies industry; Smooth muscle; Spinal cord; Sulfides; Tumor Necrosis Factor-alpha - pharmacology; United States; Japan; United States > US
• ISSN: 2314-6133; 2314-6141
• DOI: 10.1155/2019/9104680

Background. The pathogenesis of abdominal aortic aneurysm (AAA) is characterized by atherosclerosis with chronic inflammation in the aortic wall. Montelukast is a selective cys-LT 1 receptor antagonist that can suppress atherosclerotic diseases. We evaluated the in vitro properties of montelukast and its in vivo activities in an angiotensin II–infused apolipoprotein E–deficient (apoE−/−) AAA mouse model. Methods. The mouse monocyte/macrophage cell line J774A.1 was used in vitro. M1 macrophages were treated with montelukast, and gene expressions of inflammatory cytokines were measured. Macrophages were cultured with montelukast, then gene expressions of arginase-1 and IL (interleukin)-10 were assessed by quantitative polymerase chain reaction, arginase-1 was measured by fluorescence-activated cell sorting, and IL-10 concentration was analyzed by enzyme-linked immunosorbent assay. In vivo, one group (Mont, n=7) received oral montelukast (10 mg/kg/day) for 28 days, and the other group (Saline, n=7) was given normal Saline as a control for the same period. Aortic diameters, activities of matrix metalloproteinases (MMPs), cytokine concentrations, and the number of M2 macrophages were analyzed. Results. Relative to control, montelukast significantly suppressed gene expressions of MMP-2, MMP-9, and IL-1β, induced gene expressions of arginase-1 and IL-10, enhanced the expression of the arginase-1 cell surface protein, and increased the protein concentration of IL-10. In vivo, montelukast significantly decreased aortic expansion (Saline vs Mont; 2.44 ± 0.15 mm vs 1.59 ± 0.20 mm, P<.01), reduced MMP-2 activity (Saline vs Mont; 1240 μM vs 755 μM, P<.05), and induced infiltration of M2 macrophages (Saline vs Mont; 7.51 % vs 14.7 %, P<.05). Conclusion. Montelukast induces M2 macrophage polarization and prevents AAA formation in apoE−/− mice.