Montelukast, cysteinyl leukotriene receptor 1 antagonist, inhibits cardiac fibrosis by activating APJ.
Montelukast, cysteinyl leukotriene receptor 1 antagonist, inhibits cardiac fibrosis by activating APJ.
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DOI：
10.1016/j.ejphar.2022.174892
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发表时间：
2022-03
影响因子：
5
通讯作者：
Yun Wu;Chen Cui;F. Bi;Cheng-Yu Wu;Jinrui Li;Y. Hou;Ze-hong Jing;Qing-Ming Pan;Miao Cao;L. Lv;Xuelian Li;Hong-li Shan;Xin-Huan Zhai;Yu-hong Zhou
中科院分区：
文献类型：
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作者：
Yun Wu;Chen Cui;F. Bi;Cheng-Yu Wu;Jinrui Li;Y. Hou;Ze-hong Jing;Qing-Ming Pan;Miao Cao;L. Lv;Xuelian Li;Hong-li Shan;Xin-Huan Zhai;Yu-hong Zhou
孟鲁司特是半胱氨酰白三烯受体1（CysLT1R）拮抗剂，临床上用于治疗哮喘、慢性阻塞性肺疾病（COPD）和过敏性鼻炎患者。据报道，在动物研究中CysLT1R拮抗剂可以降低心血管疾病的风险。心脏纤维化是心力衰竭的主要原因之一。但人们对孟鲁司特在心脏纤维化中的作用及其潜在机制知之甚少。在横主动脉缩窄（TAC）小鼠中，孟鲁司特通过下调与纤维化相关的蛋白质，如结缔组织生长因子（CTGF）、转化生长因子β（TGF-β）和α-平滑肌肌动蛋白（α-SMA），改善心脏泵血功能并抑制心脏纤维化。 20%血清预处理后，孟鲁司特可减少新生儿心脏成纤维细胞（CF）的细胞增殖和胶原生成，同时下调TGF-β、CTGF和α-SMA的表达。分子对接方法估计了孟鲁司特与 Apelin 受体 (APJ) 的高亲和力以及孟鲁司特结合 APJ 的有效化学结构。在稳定过表达 APJ 的中国仓鼠卵巢 (CHO) 细胞中，孟鲁司特抑制毛喉素 (1 μM) 介导的环磷酸腺苷 (cAMP) 产生和细胞外信号调节激酶 1/2 (ERK1/2) 磷酸化，而这些作用可通过百日咳毒素 (PTX) 预处理逆转。 APJ沉默破坏了孟鲁司特在CFs预处理中血清20%的作用。因此我们得出结论，孟鲁司特抑制心脏纤维化可能是由于与 APJ 介导的 Gi 信号通路的耦合，这可能是心脏纤维化的一个有前途的治疗靶点。
Montelukast, cysteinyl leukotriene receptor 1 (CysLT1R) antagonist, is used clinically for patients with asthma, chronic obstructive pulmonary diseases (COPD), and allergic rhinitis. It has been reported that CysLT1R antagonists could reduce the risks of cardiovascular diseases in animal studies. Cardiac fibrosis is one of the major causes of heart failure. But little is known about the role of Montelukast in cardiac fibrosis and its underlying mechanism. In transverse aortic constriction (TAC) mice, Montelukast improved cardiac pumping function and inhibited cardiac fibrosis by down-regulation of the proteins related to the fibrosis, such as connective tissue growth factor (CTGF), Transforming Growth Factor β (TGF-β), and Alpha-smooth muscle actin (α-SMA). Montelukast reduced cell proliferation and collagen production in neonatal cardiac fibroblasts (CFs) with the pretreatment of 20% serum, while down-regulating the expression of TGF-β, CTGF and α-SMA. Molecules docking methods estimated a high affinity of Montelukast to Apelin receptor (APJ) and an effective chemical structure for Montelukast binding APJ. In Chinese hamster ovary (CHO) cells with stable overexpressing APJ, Montelukast inhibited forskolin (1 μM)-mediated cyclic adenosine monophosphate (cAMP) production and extracellular signal-regulated kinase1/2 (ERK1/2) phosphorylation, while these effects were reversed by pertussis toxin (PTX) pretreatment. APJ silence disrupted the effects of Montelukast in CFs pretreatment by serum 20%. So we concluded that Montelukast inhibited cardiac fibrosis due presumably to the coupling to the APJ-mediated Gi signaling pathway, which may be a promising therapeutic target for cardiac fibrosis.