ATF3 Overexpression Induces Cardiac Hypertrophy and Electrical Dysfunction through Enhanced Proliferation in Zebrafish

Activating transcription factor 3 (ATF3) is a key regulator of gene expression in response to physiological stress across various tissues. Although its abnormal expression has been linked to cardiac dysfunction, the precise mechanisms by which ATF3 influences cardiac pathology remain unclear, with conflicting findings in the literature. To address this, we developed a cardiac-specific ATF3-expressing zebrafish line, Tg (myl7:ATF3), using the zebrafish model as a well-established vertebrate system for cardiovascular research. Compared to wild-type (WT) siblings, Tg (myl7:ATF3) zebrafish exhibited significant pathophysiological changes, including cardiac hypertrophy and features resembling hypertrophic cardiomyopathy (HCM). Histological analysis revealed increased fibrotic scarring, sarcomere disorganization, and elevated expression of heart failure gene markers (nppa and nppb). Notably, electrocardiogram (ECG) measurements showed that ATF3 overexpression led to symptoms resembling Long QT Syndrome (LQTS), indicating electrical dysfunction. Transcriptome analysis further revealed downregulation of apoptosis-related genes and upregulation of proliferation-related genes in transgenic zebrafish hearts. These findings suggest that stress-induced ATF3 expression contributes to cardiac hypertrophy through enhanced cardiomyocyte proliferation, providing novel insights into its role in cardiovascular disease progression. Overall design: Cardiac tissue samples were collected from a transgenic zebrafish line with cardiac-specific overexpression of ATF3 (Tg(myl7:ATF3)) and age-matched wild-type (WT) siblings. RNA samples were harvested at two developmental stages—4 months post-fertilization (mpf) and 12 mpf—to investigate both early and progressive effects of ATF3 overexpression. Each group included three biological replicates. QuantSeq 3' mRNA sequencing was performed to evaluate transcriptomic changes associated with ATF3-induced cardiac hypertrophy and dysfunction. Wild-type samples serve as controls.