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Fimasartan, an Angiotensin II Receptor Antagonist, Ameliorates an in Vivo Zebrafish Model of Heart Failure

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Fimasartan, an Angiotensin II Receptor Antagonist, Ameliorates an in Vivo Zebrafish Model of Heart Failure ORIGINAL ARTICLE Korean J Intern Med 2020;35:1400-1410 https://doi.org/10.3904/kjim.2019.038 Fimasartan, an angiotensin II receptor antagonist, ameliorates an in vivo zebrafish model of heart failure Hailian Quan1,*, Gyu Chul Oh2,3,*, Seung Hyeok Seok1, and Hae-Young Lee2,3 1Department of Microbiology and Background/Aims: Angiotensin II in the failing heart initially helps to maintain Immunology, Institute of Endemic cardiac output and blood pressure, but ultimately accelerates its deterioration. Disease, 2Department of Internal Medicine, Seoul National University In this study, we established a model of arrhythmia-induced heart failure (HF) College of Medicine, Seoul; in zebrafish and investigated the role of renin-angiotensin-aldosterone system 3Department of Internal Medicine, Seoul National University Hospital, (RAAS) modulation by using an angiotensin II type 1 receptor blocker, fimasar- Seoul, Korea tan, through the assessment of cellular and physiologic responses, morbidity, and mortality. Methods: HF was induced in zebrafish larvae by exposure to 20 μM terfenadine. Morphologic, physiologic, and functional parameters were assessed in the pres- ence or absence of fimasartan treatment. Received : January 24, 2019 Results: Zebrafish exposed to terfenadine showed marked dilatation of the ven- Revised : May 30, 2019 tricle and reduced systolic function. Treatment with terfenadine was associated Accepted : June 4, 2019 with 10-fold higher expression of atrial natriuretic peptide (p < 0.001 vs. vehicle), Correspondence to increased p53 mRNA expression, and chromatin fragmentation in the TUNEL Hae-Young Lee, M.D. assay, all of which were significantly reduced by fimasartan treatment. Moreover, Department of Internal Medicine, Seoul National fimasartan improved fractional shortening (terfenadine + fimasartan 16.9% ± 3.1% University Hospital, 101 Daehak- vs. terfenadine + vehicle 11.4% ± 5.6%, p < 0.05) and blood flow (terfenadine + fima- ro, Jongno-gu, Seoul 03080, sartan 479.1 ± 124.1 nL/sec vs. terfenadine + vehicle 273.0 ± 109.0 nL/sec, p < 0.05). Korea Finally, treatment with fimasartan remarkably reduced mortality (terfenadine + Tel: +82-2-2072-0698 Fax: +82-2-3674-0805 fimasartan 36.0% vs. terfenadine + vehicle 96.0%, p < 0.001). E-mail: [email protected] Conclusions: Fimasartan effectively protected against the progression of HF in https://orcid.org/0000-0002- zebrafish by improving hemodynamic indices, which improved survival. A reduc- 9521-4102 tion in apoptotic cell death and an improvement in hemodynamics may be the Seung Hyeok Seok, Ph.D. mechanisms behind these effects. Further human studies are warranted to evalu- Department of Microbiology and ate the possible role of fimasartan in the treatment of HF. Immunology, Seoul National University College of Medicine, 103 Daehak-ro, Jongno-gu, Seoul Keywords: Heart failure; Angiotensin receptor blockers; Renin angiotensin sys- 03080, Korea tem; Zebrafish; Terfenadine Tel: +82-2-740-8302 Fax: +82-2-763-5206 E-mail: [email protected] https://orcid.org/0000-0002- INTRODUCTION more than one million patients hospi- 4315-0688 talized every year in the United States *These authors contributed Heart failure (HF) affects approximate- and Europe [1]. In the United States, HF equally to this work. ly 26 million people worldwide, with accounted for one out of nine deaths in Copyright © 2020 The Korean Association of Internal Medicine pISSN 1226-3303 This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/ eISSN 2005-6648 by-nc/4.0/) which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original work is properly cited. http://www.kjim.org Quan H, et al. Role of fimasartan in zebrafish HF model 2013 [2]. Owing to the aging population, the prevalence hours light:dark cycle, and were fed three times daily of HF is increasing [3]. Despite the development of new with Artemia (INVE, Dendermonde, Belgium). To visu- pharmacotherapy agents for HF, it remains a serious alize the heart chambers, a transgenic strain of zebrafish health problem and is associated with high mortality larvae that expresses green fluorescent protein (GFP) ex- and significant medical costs [4,5]. clusively in the cardiac myosin light chain 2 (cmlc2) [Tg The goals of therapy for patients with advanced HF (cmlc2:gfp)] was used [17]. Tg (cmlc2:gfp) lines were kindly are to improve survival, slow disease progression, and provided by the zebrafish Organogenesis Mutant Bank alleviate symptoms. Renin-angiotensin-aldosterone sys- in Korea. All animal study protocols were approved by tem (RAAS) blockers, such as angiotensin converting en- the Institutional Animal Care and Use Committee of zyme (ACE) inhibitors and angiotensin receptor block- Seoul National University (SNU-150330-3). ers (ARBs), are commonly used to achieve these goals; they decrease preload and make it easier for the heart to Chemical treatment of zebrafish pump blood. However, the use of ACE inhibitors is lim- To maintain the optical clarity of embryos, the egg wa- ited by the common side effects, such as cough; there- ter was supplemented with 0.003% 1-phenyl-2-thiourea fore, ARBs are potential alternative treatments [6]. (Sigma, St. Louis, MO, USA) at 24 hours post-fertilization Fimasartan is the ninth and the most recent ARB to (dpf). For all experiments excluding survival analysis, be approved by the Korean Food and Drug Association the larvae were transferred into 6-well microplates and as an antihypertensive agent [7-9]. In previous studies, egg water was replaced with a solution containing 20 μM fimasartan was shown to exert protective effects in ani- terfenadine (Sigma) or vehicle (0.1% dimethyl sulfoxide mal models of myocardial ischemia: the suppression of [DMSO]) for 12 hours at 3 days dpf. After terfenadine apoptosis [10] and the prevention of intimal thickening treatment, fimasartan (Boryung Pharm Co. Ltd., Seoul, and plaque rupture [11]. Furthermore, fimasartan has Korea) was added to the treatment group for 12 hours been reported to prevent doxorubicin-induced cardio- before the analysis was performed. myopathy and improve survival [12]. Therefore, fimasar- tan is regarded as a potential candidate for the attenua- Cardiac morphology tion of HF. After 12 hours treatment with fimasartan, wild-type Recently, in vivo chemical screening in a zebrafish zebrafish were anesthetized with 0.04% tricaine (Sig- model of HF has emerged as a rapid and efficient meth- ma) for 1 minute and images were obtained by using a od to identify lead compounds that modulate specific stereomicroscope (M165 FC, Leica, Wetzlar, Germany) biological processes [13,14]. We have also previously re- for morphologic observation. Tg (cmlc2:gfp) larvae were ported a zebrafish model of dilated cardiomyopathy in- immersed in 0.15% low-melt agarose and transferred duced by brief treatment with terfenadine [15]. to a confocal dish to visualize the movement of cardi- In this study, we hypothesized that treatment with ac chambers by using a fluorescence microscope (Leica fimasartan exerted protective effects against the devel- AF2000). The atrial area was calculated by using Im- opment of HF and improved survival through the pre- ageJ graphical analysis software (National Institutes of vention of apoptotic cell death in a terfenadine-induced Health, Bethesda, MD, USA). At minimum, five different in vivo zebrafish model of HF. larvae in each group were analyzed. Functional assessment METHODS Fractional shortening (FS) was calculated from the ven- tricular diastolic and systolic diameters, as measured Zebrafish husbandry and breeding from time-lapse images collected intervals of 0.16 sec- Zebrafish (Danio rerio) embryos were maintained in egg onds. Long-axis diameters were acquired from still im- water at 28.5ºC in an automatic circulating tank system ages by using ImageJ software and FS was calculated in accordance with instructions from The Zebrafish Book from the following formula: FS = (VDD – VSD) / VDD × [16]. Adult fish were maintained at 28°C under a 14:10 100% (VDD, ventricle diastolic diameter; VSD, ventricle https://doi.org/10.3904/kjim.2019.038 www.kjim.org 1401 The Korean Journal of Internal Medicine Vol. 35, No. 6, November 2020 systolic diameter). TUNEL assay The blood flow and time interval between heartbeats The fragmentation of DNA in apoptotic cells was iden- were also assessed. After exposure to the drug, the lar- tified by the terminal deoxynucleotide transferase-me- vae were anesthetized with 0.04% tricaine for 1 minutes, diated dUTP nick-end labeling (TUNEL) assay using the transferred to a confocal dish, and visualization by using In Situ Cell Death Detection Kit, POD (Roche Diagnos- a stereomicroscope (Leica M165 FC) fitted with a high- tics GmbH, Mannheim, Germany). Zebrafish larvae were speed video camera. The orientation of the larva was fixed in 4% paraformaldehyde (PFA) overnight at 4°C. Af- then adjusted very gently so that the larva lay on its side ter fixation, excess 4% PFA was removed by five rinses in with its head to the left. First, the camera was positioned phosphate-buffered saline with Tween 20 (PBST), each to capture the whole heart at a rate of 30 frames per sec- of 5 minutes, and 100% methanol was added. The lar- onds (fps), and then repositioned to capture the dorsal vae were incubated at –20°C for at least 30 minutes, and aorta and caudal to the swim bladder at 120 fps. The rehydrated in a graded methanol series (75%, 50%, 25%, camera in both positions was independently focused on and twice in 0%). The larvae were then incubated with the respective regions of interest to ensure optimal im- proteinase K (50 μg/mL in PBST) for 30 minutes at room age quality, and set to record simultaneously. temperature (RT), and excess proteinase K was removed To determine atrioventricular (AV) synchrony, videos by two rinses in PBST, each of 5 minutes. The larvae of the heart were analyzed by using MicroZebraLab ver- were re-fixed in 4% PFA for 20 minutes at RT and excess sion 3.5 (ViewPoint, Lyon, France).
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