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Therapeutic Potential of Montelukast, Cysteinyl Leukotriene Receptor 1 Antagonist, for Aortic Aneurysm

2019; Elsevier BV; Volume: 58; Issue: 6 Linguagem: Inglês

10.1016/j.ejvs.2019.06.1064

1532-2165

Yohei Kawai, Yuji Narita, Aika Ogata, Akihiko Usui, Kimihiro Komori,

IL-33, ST2, and ILC Pathways

Introduction - The pathogenesis of aortic aneurysm (AA) is characterized by destruction of extracellular matrix with chronic inflammation in aortic wall. The current available treatment of AA is either open surgical repair or endovascular repair, but there are still some surgical disadvantages and complications, and also surgically inapplicable cases for various condition of the patient. Therefore, it is necessary to develop alternative noninvasive therapy for AA. Recently, leukotriene D4 (LTD4), which derives from the 5-lipoxygenase cascade, has been implicated in the pathogenesis of AA. LTD4 has potent pro-inflammatory biological activities through cysteinyl leukotriene (cysLT) receptor 1. Montelukast is a selective cysLT receptor 1 antagonist possessing anti-inflammatory effects and has been widely used for treatment of inflammatory diseases such as asthma and allergic rhinitis. However, little information is available about the effect of montelukast for AA formation. In this study, we evaluated the in vitro properties of montelukast and its in vivo activities in angiotensin II (AT II) –induced apolipoprotein E-deficient (apoE−/−) AA mice models. Methods - The J774A1 murine macrophage cells were stimulated by tumor necrosis factor-α (TNF-α) for 24h and then treated with or without montelukast (2 micro M or 20 micro M) for 24h in vitro. Gene expressions of inflammatory cytokines from macrophages, such as matrix metalloproteinase (MMP)-2, MMP-9, interleukin (IL)-1β, nuclear factor kappa B (NF-κB), monocyte chemotactic protein (MCP)-1 and TNF-α, were measured and normalized by using GAPDH as an internal standard. In vivo, AA was induced in apoE−/− mice by AT II-infusion for 28 days through subcutaneously implanted osmotic mini-pump. Mice were randomly divided into 2 groups. One group (n=7, group M) orally received montelukast (10mg/kg/day) once a day for 28 days and the other group (n=7, group S) was given vehicle during the same period. Mice were sacrificed at 28 days after administration. Aortic diameter, medial elastin area, MMP-2 and MMP-9 enzymatic activity and cytokine concentrations were measured in obtained aortic tissue. Results - Montelukast significantly suppressed MMP-2 (control vs 20 micro M; 0.94 vs 0.64, p<0.01), MMP-9 (control vs 20 micro M; 26.5 vs 16.7, p<0.05), IL-1β (control vs 20 micro M; 1.37 vs 0.56, p<0.01) and NF-κB (control vs 20 micro M; 0.97 vs 0.68, p<0.01) expression in macrophages in vitro. In vivo, the aortic diameters of group M were significantly decreased compared to group S (group S vs M; 2.44 vs 1.59 (mm), p<0.01). Montelukast administration significantly suppressed incidence of AA (group S vs M; 100 vs 14.3 (%), p<0.01). The medial elastin area in group M was significantly protected from degradation (group S vs M; 45.0 vs 56.1 (%), p<0.05). The enzymatic activities of MMP were reduced in group M and inflammatory cytokines were also down-regulated in group M. Conclusion - Our results suggest that the anti-asthmatic drug montelukast is effective for prevention of AA formation induced by AT II in apoE−/− mice. CysLT receptor 1 ligands induce the release of MMPs and inflammatory mediators from macrophages in aortic wall, leading to AA. We revealed that this mechanism could be inhibited by montelukast. Montelukast has therapeutic potential in preventing the development of AA and might become as a novel anti-aneurysm agent.