Inhibition of cardiac hypertrophy by aromadendrin through down-regulating NFAT and MAPKs pathways

https://doi.org/10.1016/j.bbrc.2018.10.143Get rights and content

Highlights

  • Aromadendrin prevented cardiac hypertrophy and dysfunction after pressure-overload.

  • ARO suppressed protein synthesis and fetal gene reactivation in vitro.

  • ARO attenuated cardiac fibrosis and oxidative stress in cardiac hypertrophy.

  • ARO suppressed NFAT nuclear translocation and inhibited MAPKs pathway activations.

  • ARO has the potential application prospects for cardiac hypertrophy treatment.

Abstract

Cardiac hypertrophy is a maladaptive response to pressure overload and it's an important risk factor for heart failure and other adverse cardiovascular events. Aromadendrin (ARO) has remarkable anti-lipid peroxidation efficacy and is a potential therapeutic medicine for the management of diabetes and cardiovascular diseases. In this study, we established the cardiac hypertrophy cell model in rat neonatal ventricular cardiomyocytes (RNVMs) with phenylephrine. The cell model was characterized by the increased protein synthesis and cardiomyocyte size, which can be normalized by ARO treatment in both concentration- and time-dependent manner. In transverse aortic constriction (TAC) induced cardiac hypertrophy model, ARO administration improved the impairment of cardiac function and alleviated the cardiac hypertrophy indicators, like ventricular mass/body weight, myocyte cross-sectional area, and the expression of ANP, BNP and Myh7. ARO treatment also suppressed the cardiac fibrosis and the correlated fibrogenic genes. Our further investigation revealed ARO could down-regulate pressure overload-induced Malondialdehyde (MDA) and 4-HNE expression, restore the decrease of GSH/GSSG ratio, meanwhile prevent nuclear translocation of NFAT and the activation of MAPKs pathways. Collectively, ARO has a protective effect against experimental cardiac hypertrophy in mice, suggesting its potential as a novel therapeutic drug for pathological cardiac hypertrophy.

Introduction

Cardiac hypertrophy is an adaptive response to various stimuli. Both physiological and pathological hypertrophy involve enlargement of individual cardiomyocytes, but the characteristics of each type of hypertrophy are distinct [1]. Pathological hypertrophy is a response to long-term hemodynamic load, such as hypertension, heart aortic stenosis and myocardial infarction [2]. It is initially induced as a compensatory response with a concentric growth of the ventricle. If this response is not counteracted, progressive myocardial insults will eventually lead to heart failure [3]. Pathological cardiac hypertrophy is a major and independent risk factor for heart failure. There is no effective treatment strategy to date, which motivates researchers around the world to explore the underlying mechanism and viable strategies [4,5].

Cardiac hypertrophic adaptations are involved in inflammation, fibrosis, oxidative stress, reactivation of fetal gene expression, and accompanied by alteration of a complex cascade of signaling pathways [6]. Generally, cellular “redox homeostasis” is vital to maintain the healthy physiology of cardiomyocytes. Reactive oxygen species (ROS) generated during excessive oxidative stress, are responsible for the pathophysiology of cardiac hypertrophy and fibrosis [7,8]. Antioxidant-based therapies could scavenge the free radicals and other toxic radicals, which have shown a therapeutic impact in cardiac hypertrophy [9]. ROS is a major stimulant for the signal transduction in cardiomyocytes pathological conditions by activating nuclear factor of activated T cells (NFAT) and mitogen-activated protein kinases (MAPKs) pathway [10,11]. In the past decade, a growing number of studies have suggested that NFAT and MAPKs pathway are vital in the development of cardiac hypertrophy. Mechanically, they can enhance the expression of hypertrophy-related genes and accelerate cardiac dysfunction [12,13].

Chinese herbs display tremendous promise in combating various cardiovascular diseases, including hypertension and heart failure [14,15]. Aromadendrin (ARO) is a type of flavonoid derived from Chionanthus retusus, which demonstrated tremendous anti-inflammatory, anti-oxidant and anti-proliferative activities [[16], [17], [18], [19]]. Recently, ARO was reported to stimulate glucose uptake and ameliorate insulin resistance, suggesting that it may be a potential therapeutic medicine for the management of type 2 diabetes [20]. Given the reported pharmacological activity, it is reasonable to speculate a protective potential of ARO in cardiac hypertrophy. Here, we tested the effects of ARO on transverse aortic constriction (TAC) induced cardiac hypertrophy and elucidated its underlying mechanisms.

Section snippets

Animals and TAC models

Ten-to-twelve-week-old male C57BL/6 mice were used in this study. All animal experimental procedures were carried out in accordance with the Guide for the Care and Use of Laboratory Animals and were approved by the Institutional Animal Care and Use Committee of Shandong University. Mice cardiac hypertrophy model were established by transverse aortic constriction (TAC) surgeries as previously described [21]. ARO treatment (0.2% in maintaining feed) was started immediately after TAC surgery.

Echocardiography

After

ARO suppressed protein synthesis and cardiomyocytes hypertrophy induced by PE

H3-Leucine incorporation assay was utilized to measure the rate of protein synthesis in cell culture. As Fig. 1A showed, ARO had no effects on protein synthesis at baseline. However, ARO normalized the up-regulated protein synthesis after PE treatment (20 μM, 48 h) in a concentration-dependent manner. We also observed that PE increased the H3-Leucine incorporation in a time-dependent manner. The increase was significantly blocked by 100 μM ARO treatment (Fig. 1B). Similarly, α-Actinin

Discussions

In this study, we found the protective potential of ARO in cardiac hypertrophy and elucidated its mechanism based on cell and animal experiments. In vitro, ARO inhibited PE-induced protein synthesis, suppressed the increased cardiomyocyte sizes, and reduced ANP, BNP promoter activity. In vivo, ARO prevented the increase of ventricular/TL and cardiac myocyte cross-sectional area in TAC mice model. ARO attenuated fibrosis and excessive oxidative stress, further prevented cardiac dysfunction

Conflicts of interest

The authors declare that there are no conflicts of interest.

Acknowledgments

This study was supported by grants from the National Natural Science Foundation of China (No.81300162; No.81300459); and Natural Science Foundation of Shandong Province (No. ZR2016HM48; No.2013ZRE27112). Project funded by China Postdoctoral Science Foundation (No.2014M551921; No.2017M610429; No.2018T110694) and the International Postdoctoral Exchange Fellowship Program.

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    Sumei Cui and Yuqian Cui contributed equally to this work.

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