ATF3 overexpression is associated with cardiac hypertrophy and electrical dysfunction accompanied by enhanced cardiac cell proliferation in zebrafish

Activating transcription factor 3 (ATF3) is a crucial regulator of gene expression in response to physiological stress across various tissues. Abnormal ATF3 expression is associated with cardiac dysfunction; however, the mechanisms by which it affects cardiac pathology remain unclear. In this study, we developed a cardiac-specific ATF3-expressing zebrafish line, Tg(myl7:ATF3), using a well-established vertebrate model for cardiovascular research to investigate the role of human ATF3 in the zebrafish heart. We conducted morphological assessments, immunofluorescence staining, electrocardiography, and transcriptome analysis on transgenic and wild-type zebrafish. Compared to wild-type siblings, Tg(myl7:ATF3) zebrafish exhibited significant pathophysiological changes, including cardiac hypertrophy and features resembling hypertrophic cardiomyopathy. Histological analysis revealed increased fibrotic scarring and disorganized sarcomeres. Electrocardiogram measurements indicated that ATF3 overexpression induced symptoms resembling long QT syndrome, suggesting electrical dysfunction. Transcriptome analysis demonstrated downregulation of apoptosis-related genes and upregulation of proliferation-related genes in the hearts of transgenic zebrafish. These findings suggest that ATF3 expression is associated with cardiac hypertrophy accompanied by increased proliferation of cardiac cells, including cardiomyocytes. The findings of this study provide novel insights into the role of ATF3 in cardiovascular disease progression.