Biochemical and Biophysical Research Communications
Inhibition of cardiac hypertrophy by aromadendrin through down-regulating NFAT and MAPKs pathways
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.
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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.