Montelukast, cysteinyl leukotriene receptor 1 antagonist, inhibits cardiac fibrosis by activating APJ☆
Introduction
Cysteinyl leukotrienes (CysLTs) are a class of inflammatory mediator which is the products of arachidonic acid metabolism via the 5-lipoxygenase pathway (Henderson et al., 2006; Prescott et al., 2020). Montelukast, a cysteinyl leukotriene receptor 1 (CysLT1R) antagonist, is mainly used for the prevention and long-term treatment of asthma in a clinic, to prevent exercise-induced bronchoconstriction, and also for relieving allergic rhinitis (Muz et al., 2006; Rubinstein et al., 2004). Montelukast has also been applied for patients with cystic fibrosis to reduce airway cysteinyl leukotriene levels, which may contribute to airway inflammation (Peng et al., 2017; Shimbori et al., 2011; Spencer et al., 1992). Montelukast inhibits the oxidant-induced tissue fibrosis via balancing oxidant-antioxidant status and regulating the generation of pro-inflammatory mediators (Schmitt-Grohe et al., 2002; Sener et al., 2007). Therefore, we have a strong reason to believe that the anti-fibrosis effects of Montelukast are mainly due at least partially to interrupt inflammatory processes, rather than to directly antagonize its receptor, CysLT1R. Montelukast-mediated regulation of inflammatory responses includes inhibition of the enzymes 5-lipoxygenase (Ramires et al., 2004), histone acetyltransferase (HAT) (Tahan et al., 2008), and cAMP phosphodiesterase (Anderson et al., 2009), as well as inhibition of eosinophil adhesion to vascular endothelium and migration (Robinson et al., 2008). However, little is known about the effect of Montelukast on heart diseases, especially cardiac fibrosis, or the mechanisms underlying this process.
Apelin receptor (APJ) has strong homology with angiotensin II (Ang II) type 1 receptor (AT1R) (transmembrane domain is 54% and the entire sequence is 30%) (Cayabyab et al., 2000; Tatemoto et al., 1998). Apelin, the endogenous ligand of APJ, is an important protective regulator by binding and activating APJ, which is an exactly opposite effect by binding to AT1R. Apelin/APJ system has a wide tissue distribution in the heart as well as in other organs or tissue including the brain, lung, vessels, and adipose tissue (Koguchi et al., 2012; Zhong et al., 2017). Apelin/APJ system plays diverse roles in cardiovascular system, such as enhancing cardiac contractility, inhibiting cardiomyocyte hypertrophy, inhibiting atherosclerosis and cardiac fibrosis (Parikh et al., 2018; Zhang et al., 2016). Apelin significantly reduces Ang II-induced cardiac hypertrophy by reducing the cell size and protein content of cardiomyocytes (Zhang et al., 2017). Apelin eliminates Ang II-induced cardiovascular fibrosis by inhibiting PAI-1 (Siddiquee et al., 2011). Our previous studies have shown that Apelin-13 inhibits Ang II-induced fibrosis through a TGFβ-CTGF-dependent mechanism (Zhou et al., 2016). Apelin/APJ constitutes a novel endogenous peptide/GPCR system and promises as an anti-fibrotic target for the development of novel therapeutic agents.
Molecular docking methods have broadly been used in modern drug design and to explore the ligand conformations adopted within the binding sites of macromolecular targets (Fang, 2012; Wilson and Lill, 2011). Using this approach, a higher affinity and an effective chemical structure of Montelukast for binding to APJ have been estimated in the current study. Therefore, we investigated the regulatory effect of Montelukast and the mechanism on cardiac fibrosis in vivo and in vitro.
Section snippets
Animals and chemicals
The study was approved by the Institutional Animal Care and Use Committee of Harbin Medical University, P.R. China (No. HMUIRB3022621). This experiment was conducted in accordance with the Guide for the Care and Use of Laboratory Animals published by the US National Institutes of Health (NIH Publication No. 85–23, revised 1996). Male C57BL/6 mice of 20–25 g were provided by the Experimental Animal Center of Harbin Medical University.
Montelukast (HY-13315, MCE, Monmouth Junction, USA) stock
Montelukast treatment improves cardiac functional and morphological alterations in a TAC model of cardiac fibrosis
To determine the effect of Montelukast on cardiac function, echocardiography was carried out in sham control and TAC model mice in the presence of 1, 2, and 4 mg/kg of Montelukast. The results showed that Montelukast increased the survival of mice induced by TAC and improved the heart remodeling of the mice induced by TAC as shown in Fig. 1A and B (P < 0.01, n = 4 compared with TAC model). the cardiac pump function was significantly improved by Left ventricular ejection fraction (EF) and
Discussion
The major contribution of the current observation is to identify for the first time that Montelukast could improve cardiac pumping function in the TAC mouse model due presumably to the inhibition the cardiac fibrosis experimentally in vivo and in vitro condition. In addition, the observation has also demonstrated the binding property between Montelukast and APJ and the direct APJ activation, which consequently inhibits FSK-stimulated cAMP production and induction of ERK1/2 phosphorylation APJ
Conflicts of interest
All authors declare that they have no conflicts of interest or financial conflicts to disclose.
CRediT authorship contribution statement
Yun Wu: Participated in research design, Conducted experiments, Performed data, Formal analysis. Chen Cui: Conducted experiments. Fang-fang Bi: Conducted experiments, Performed data, Formal analysis. Cheng-yu Wu: Conducted experiments. Jin-rui Li: Conducted experiments. Yu-meng Hou: Conducted experiments. Ze-hong Jing: Conducted experiments. Qing-ming Pan: Conducted experiments. Miao Cao: Conducted experiments. Hong-li Shan: Wrote or contributed to the writing of the manuscript. Xin Zhai:
Declaration of competing interest
All authors declare that they have no conflicts of interest or financial conflicts to disclose.
Acknowledgement
This work was supported by National Natural Science Foundation of China, China (81872863 and 81861128022), the Major Scientific Fund Project of Heilongjiang Province (ZD2019H001).
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These authors contributed equally: Yun Wu, Chen Cui.