Korean J Intern Med. 2020;35(6):1400-1410.

Fimasartan, an angiotensin II receptor antagonist, ameliorates an in vivo zebrafish model of heart failure.

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제1저자 Hailian Quan, 오규철 · 교신저자 석승혁, 이해영

PMID 32164398 PMC7652659 DOI 10.3904/kjim.2019.038 IF 2.2 순환기내과

소속 (3)

Department of Microbiology and Immunology, Institute of Endemic Disease, Seoul National University College of Medicine, Seoul, Korea.
Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea.
Department of Internal Medicine, Seoul National University Hospital, Seoul, Korea.

Abstract

BACKGROUND/AIMS Angiotensin II in the failing heart initially helps to maintain cardiac output and blood pressure, but ultimately accelerates its deterioration. In this study, we established a model of arrhythmia-induced heart failure (HF) in zebrafish and investigated the role of renin-angiotensin-aldosterone system (RAAS) modulation by using an angiotensin II type 1 receptor blocker, fimasartan, 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 presence or absence of fimasartan treatment.

RESULTS Zebrafish exposed to terfenadine showed marked dilatation of the ventricle and reduced systolic function. Treatment with terfenadine was associated with 10-fold higher expression of atrial natriuretic peptide (p < 0.001 vs. vehicle), increased p53 mRNA expression, and chromatin fragmentation in the TUNEL assay, all of which were significantly reduced by fimasartan treatment. Moreover, fimasartan improved fractional shortening (terfenadine + fimasartan 16.9% ± 3.1% vs. terfenadine + vehicle 11.4% ± 5.6%, p < 0.05) and blood flow (terfenadine + fimasartan 479.1 ± 124.1 nL/sec vs. terfenadine + vehicle 273.0 ± 109.0 nL/sec, p < 0.05). Finally, treatment with fimasartan remarkably reduced mortality (terfenadine + fimasartan 36.0% vs. terfenadine + vehicle 96.0%, p < 0.001).

CONCLUSION Fimasartan effectively protected against the progression of HF in zebrafish by improving hemodynamic indices, which improved survival. A reduction in apoptotic cell death and an improvement in hemodynamics may be the mechanisms behind these effects. Further human studies are warranted to evaluate the possible role of fimasartan in the treatment of HF.

Keywords

Angiotensin receptor blockersHeart failureRenin angiotensin systemTerfenadineZebrafish

Figures

**Figure 1.** Fimasartan ameliorates heart failure in terfenadine-induced zebrafish larvae. (A–C) Microscopic images of zebrafish hearts. In comparison with (A) vehicle, (B) terfenadine-treated larvae show an increase in heart size, edema (*) and venous congestion (**). (C) Treatment with fimasartan ameliorates changes brought on by terfenadine. (D) Changes in ventricular diastolic diameter and (E) ventricular FS (n = 5 for each group). (F) Levels of *nppb* mRNA expression (n = 20 for each group). Scale bar = 1 mm. Error bars represent standard deviation. VDD, ventricular diastolic diameter; FS, fractional shortening; dpf, days post-fertilization; Ter, terfenadine; FMS, fimasartan; *nppb*, natriuretic peptide b. ^ap < 0.05, ^bp < 0.001.

**Figure 2.** Fimasartan promotes recovery of cardiac output. (A) Study design. (B) Poincaré plot showing heart beat variations. (C) Blood flow velocity of zebrafish larvae (n = 5 for each group). Error bars represent standard deviation. Ter, terfenadine; dpf, days post-fertilization; FMS, fimasartan. ^ap < 0.05.

**Figure 3.** Fimasartan improves atrioventricular dyssynchrony. (A) Time-lapse images showing the dynamic heartbeat of zebrafish larvae. (B) Atrioventricular ratio of zebrafish larvae. (C) Atrial area of zebrafish larvae. Scale bar = 0.5 µm. Error bars represent standard deviation (n = 3 for each group). dpf, days post-fertilization; Ter, terfenadine; FMS, fimasartan. ^ap < 0.05, ^bp < 0.01.

**Figure 4.** Fimasartan prevents apoptotic cell death. (A–C) Whole-mount TUNEL staining of zebrafish larvae. (A) Brown-color (arrows) indicates TUNEL-positive apoptotic cells. (B) Apoptotic cells are dramatically increased in terfenadine-treated larvae, (C) while treatment with fimasartan effectively decreased apoptotic cells. (D) Quantification of TUNEL-positive cells (n = 4 for each group). (E) Levels of p53 mRNA expression (n = 20 for each group). Scale bar = 1 mm. Error bars represent standard deviation. dpf, days post-fertilization; Ter, terfenadine; FMS, fimasartan. ^ap < 0.01, ^bp < 0.001.

**Figure 5.** Fimasartan improves motility and survival. (A) Mobility study design. (B) Distance travelled by zebrafish larvae (n = 10 for each group). (C) Movement trajectories of zebrafish larvae (n = 10). Each color represents the trajectories of zebrafish larvae over 20 seconds. (D) Survival curve of zebrafish larvae (n = 25 for each group). Ter, terfenadine; dpf, days post-fertilization; FMS, fimasartan. ^ap < 0.01, ^bp < 0.001.

그림 출처: PubMed Central 공개 논문 (PMC7652659)

Conflict of interest statement

No potential conflict of interest relevant to this article was reported.

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