Abstract 18712: Fimasartan, an Angiotensin II Receptor Antagonist, Improves Heart Failure and Survival in Zebrafish Model

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Abstract

We developed zebrafish heart failure (HF) model and investigated the protecting role of an angiotensin II receptor antagonist, fimasartan (FMS, 200 μM).

HF was induced by short term (12 hr) treatment of a known cardiotoxic drug, terfenadine (Ter, 20μM) in zebrafish larvae at 72 hour post-fertilization. Markedly dilated ventricles, swelling of the chambers and reduced systolic function, all of which were the typical features of human HF, were observed in transgenic cmlc:GFP zebrafish, which express green fluorescent protein (GFP) in the cardiomyocytes. However, FMS pretreatment preserved systolic function with the fractional shortening (vehicle 37.3±2.1 vs Ter 8.4±0.7 vs Ter with FMS 21.7±2.1, p<0.01HH). To demonstrate that Ter-induced cardiac arrhythmia, we used a cardiovascular automatic analysis system (MicroZebraLabTM, Viewpoint) to determine time interval of heart beat and mean erythrocyte cell velocity (nl/second). A significant increase in heart beat irregularity (p<0.01, vehicle 0.1±0.1 vs. Ter 0.5±0.3 second) and decrease in blood flow (p<0.05, vehicle 917.5±218.6 vs. Ter 198.6±19.1 nl/second) were found in Ter-treated zebrafish, which were significantly protected by FMS (0.2±0.1 second, p<0.01 and 786.8±86.4 nl/second, p<0.01) (Figures).

Ter treatment were associated with a ten-fold higher expression of atrial natriuretic peptide (p<0.01 vs. vehicle) and increased p53 mRNA expression and chromatin fragmentation by TUNEL assay, all of which were significantly reduced by FMS treatment. Lastly, Ter treatment marked impaired zebrafish survival, however, FMS treatment increased the survival rate by 56% (p<0.01) compared with Ter.

These findings demonstrated that the zebrafish model could be a tractable HF model for drug discovery and FMS treatment protects HF development and improves survival by the prevention of apoptotic cell death.

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