A Conserved Mechanism of Cardiac Hypertrophy Regression through FoxO1

Area of Science:

• Cardiovascular biology
• Molecular mechanisms of cardiac adaptation
• Comparative physiology

Background:

• Physiological cardiac hypertrophy, a reversible increase in heart muscle mass, is well-documented, but the mechanisms controlling its regression remain unclear.
• Understanding hypertrophy regression is crucial for addressing cardiac remodeling in various physiological and pathological states.

Approach:

• Utilized Burmese pythons, known for reversible cardiac hypertrophy post-feeding, to investigate regression mechanisms.
• Employed multi-omics screening and targeted analyses to identify key molecular players.
• Developed an in vitro cardiomyocyte model to test the functional role of identified pathways.

Key Points:

• Forkhead box protein O1 (FoxO1) signaling and autophagy were downregulated during hypertrophy and reactivated during regression in pythons.
• FoxO1 inhibition blocked regression in vitro, while FoxO1 activation promoted regression in an autophagy-dependent manner.
• FoxO1 activation and increased autophagy were observed during regression in mammalian models of exercise and pregnancy-induced hypertrophy.

Conclusions:

• FoxO1-dependent autophagy is a conserved mechanism for the regression of physiological cardiac hypertrophy.
• This finding provides a novel molecular target for understanding and potentially manipulating cardiac remodeling across species.