The Tet3 degrader Bobcat339 ameliorates isoprenaline induced cardiac fibrosis and heart failure: animal and transcriptomic studies.

AIMS: Aberrant cardiac fibrosis contributes to heart failure. It has been previously shown that the DNA dioxygenase ten-and-eleven translocator 3 (TET3) promotes cardiac fibrosis and heart failure. In the present study we examined the effects of a small-molecule TET3 degrader Bobcat339 on cardiac fibrosis and cellular transcriptome.

METHODS AND MATERIALS: C57BL/6J mice were injected with isoprenaline (ISO) to induce cardiac fibrosis and heart failure. Cellular transcriptome was evaluated by RNA-seq and ATAC-seq.

KEY FINDINGS: Co-treatment with Bobcat339 significantly attenuated activation of cardiac fibroblasts subjected to ISO treatment. Compared to the mice injected with vehicle control, the mice injected with Bobcat339 displayed significantly amelioration of cardiac fibrosis as evidenced by histological staining, hydroxyproline levels, and expression of myofibroblast markers in the heart. Intervention with Bobcat339 rescued the mice from ISO-induced heart failure but did not influence cardiac hypertrophy. RNA-seq data indicated that Bobcat339 intervention led to massive transcriptomic alterations in cardiac fibroblasts. These changes could be attributed to, at least in part, by differential chromatin accessibility as uncovered by ATAC-seq. An integrated analysis of RNA-seq and ATAC-seq suggested that Bobcat339 primarily impacted genes regulating extracellular matrix and cytoskeletal remodeling.

SIGNIFICANCE: Our data demonstrate that Bobcat339 antagonizes ISO-induced cardiac fibrosis in mice thus affirming that TET3 could be targeted for the intervention of heart failure. In addition our data shed additional light on the mechanism whereby TET3 contributes to activation of cardiac fibroblasts to promote cardiac fibrosis and heart failure.