A zebrafish model of chronic heart failure caused by protein aggregation in heart valves.

We previously developed a unique zebrafish, tomato, expressing the red fluorescent protein DsRed under the control of the tph2 promoter. Unexpectedly, the tomato fish showed cardiac dilation and symptoms resembling those of chronic heart failure. Therefore, we investigate the pathogenesis and causes of these cardiac abnormalities. Crossbreeding suggests a link between DsRed expression and heart enlargement. Histological analysis confirms atrial dilation and thickening of the atrioventricular valve. RNA sequencing and immunohistological imaging reveal that valve thickness is due to the upregulated inflammation, cell proliferation, and epithelial-mesenchymal transition. Importantly, immunohistological staining elucidates DsRed accumulation in the atrioventricular valve, and removal of DsRed via Cre-mRNA injection rescues these heart defects. This study establishes a potential model of heart failure caused by protein aggregation in the cardiac valve. These findings highlight the potential of this transgenic zebrafish for investigating valvular heart diseases and chronic heart failure and developing new therapies.