ZFPM2 deficiency is associated with oxidative stress and autophagy via FoxO pathway suppression in cardiac development and heart failure

Abstract To investigate the role of zebrafish zfpm2a in cardiac development and maintenance of cardiac function, and to explore its potential mechanisms in heart failure (HF). The evolutionary conservation of ZFPM2 and the spatiotemporal expression patterns of zebrafish zfpm2a were analyzed. A zfpm2a knockout zebrafish line ( zfpm2a −/− ) was generated to assess developmental and cardiac phenotypes. Cardiac tissue transcriptome sequencing was performed to identify pathways regulated by zfpm2a . Resveratrol treatment was administered to H9C2 cells subjected to siRNA-mediated Zfpm2 knockdown to further elucidate the underlying mechanisms. ZFPM2 was highly conserved, and zebrafish zfpm2a was maternally expressed, with expression increasing after 48 h post-fertilization (hpf) and being enriched in the brain, heart, and swim bladder. zfpm2a knockout resulted in reduced hatching rates, impaired swimming ability, increased mortality, and significant cardiac dysfunction, including decreased heart rate, cardiac fluorescence intensity, stroke volume, fractional shortening, and ejection fraction. Transcriptome analysis indicated suppression of the FoxO signaling pathway in the hearts of zfpm2a −/− zebrafish. In H9C2 cells, Zfpm2 knockdown reduced cell viability and increased apoptosis, malondialdehyde (MDA) content, and reactive oxygen species (ROS) levels, whereas resveratrol reversed these effects. Resveratrol also increased the expression of Sirt, Foxo1/3, Bnip3, and Atg8 at both the mRNA and protein levels. ZFPM2 is essential for cardiac development and the maintenance of cardiac function. Its deficiency may contribute to HF progression by modulating the FoxO signaling pathway and altering oxidative stress and autophagy, thereby providing potential therapeutic targets for HF.