The protective role of Baz2b ablation in aging-related heart failure

Abstract Background The elderly population is increasing year by year. Aging has become an important risk factor for cardiac dysfunction and heart failure. Previous studies have found that bromodomain adjacent to zinc finger 2B (Baz2b) is closely associated with neurodegeneration, but its role in aging-related heart failure remains unclear. Purpose We aim to explore the mechanism of Baz2b in aging-induced heart failure and doxorubicin-induced heart failure. We also investigate whether Baz2b and its downstream mechanism can serve as targets for clinical intervention. Methods We injected doxorubicin intraperitoneally in Baz2b knockout and cardiac-specific Baz2b knockdown mice to produce in vivo models. The effects of Baz2b and its downstream regulators were further explored via RNA-sequence, chromatin immunoprecipitation-sequence (ChIP-seq) and assay for transposase-accessible chromatin-sequence (ATAC-seq). Besides, we elucidated the function of Baz2b in alpha-myosin heavy chain-induced myocarditis. Results we found that Baz2b expression was upregulated in both aged and doxorubicin-induced mice heart. Baz2b knockout resulted in cardiac function recovery accompanied by a decline in apoptosis in aged mice and doxorubicin-induced mice. In contrast to control mice, cardiac-specific Baz2b knockdown alleviated doxorubicin-induced cardiac dysfunction and apoptosis. Mechanistically, Baz2b was closely associated with inflammatory responses in heart. It regulates Stat1, an important inflammatory downstream regulator via H3k4me3. Furthermore, the overexpression of Stat1 was able to abolish the protective role of Baz2b in doxorubicin-induced cardiotoxicity. Besides, cardiac-specific Baz2b knockdown could alleviated myocarditis, in line with the fact that Baz2b was linked to inflammation. Conclusion Taken together, this study provides new insights that Baz2b plays an important role in aging-related heart dysfunction. Since epigenetic readers were previously unrecognized, these findings may shed on novel clinical therapeutic choice for patients with chemotherapy-induced cardiotoxicity.The schematic diagram of Baz2b in heart