Bellidifolin ameliorates isoprenaline-induced cardiac hypertrophy by the Nox4/ROS signalling pathway through inhibiting BRD4

To date, there is no effective therapy for pathological cardiac hypertrophy, which can ultimately lead to heart failure. Bellidifolin (BEL) is an active xanthone component of Gentianella acuta (G. acuta) with a protective function for the heart. However, the role and mechanism of BEL action in cardiac hypertrophy remain unknown. In this study, the mouse model of cardiac hypertrophy was established by isoprenaline (ISO) induction with or without BEL treatment. The results showed that BEL alleviated cardiac dysfunction and pathological changes induced by ISO in the mice. The expression of cardiac hypertrophy marker genes, including ANP, BNP, and β-MHC, were inhibited by BEL both in mice and in H9C2 cells. Furthermore, BEL repressed the epigenetic regulator bromodomain-containing protein 4 (BRD4) to reduce the ISO-induced acetylation of H3K122 and phosphorylation of RNA Pol II. The Nox4/ROS/ADAM17 signalling pathway was also inhibited by BEL in a BRD4 dependent manner. Thus, BEL alleviated cardiac hypertrophy and cardiac dysfunction via the BRD4/Nox4/ROS axes during ISO-induced cardiac hypertrophy. These findings clarify the function and molecular mechanism of BEL action in the therapeutic intervention of cardiac hypertrophy.