Bclaf1 drives heart failure by recruiting Srsf2 to enhance Hand2 pre-mRNA splicing and pathological hypertrophy.

Summary

This mechanistic study shows that Bclaf1 recruits Srsf2 to enhance Hand2 splicing, driving maladaptive hypertrophy and systolic dysfunction. Genetic loss or AAV9 knockdown of Bclaf1, or inhibition of Hand2, reverses heart failure phenotypes, nominating a tractable splicing axis for therapy.

Key Findings

• Bclaf1 is upregulated in human HFrEF myocardium and murine pressure-overload hearts.
• Cardiac-specific Bclaf1 overexpression induces pathological hypertrophy and systolic dysfunction; knockout or AAV9 knockdown attenuates these phenotypes.
• Bclaf1 interacts with Srsf2 to enhance Hand2 pre-mRNA splicing, increasing mature Hand2 and promoting maladaptive remodeling.
• Pharmacologic/genetic inhibition of Bclaf1 or Hand2 rescues cardiac structure and function in experimental HFrEF.

Clinical Implications

While preclinical, targeting the Bclaf1/Srsf2/Hand2 axis (e.g., antisense or small molecules) could inaugurate mechanism-based therapies for HFrEF beyond neurohormonal blockade.

Limitations

• Predominantly male murine models; sex-specific effects and long-term safety of targeting this axis remain unknown.
• Preclinical study without large-animal validation or pharmacokinetic/toxicology data.

Future Directions

Develop antisense/chemical probes to modulate Bclaf1–Srsf2–Hand2 splicing in large-animal HFrEF models; biomarker strategies to identify splicing-driven HF endotypes for trials.