Mechanical unloading activates FoxO3 to trigger Bnip3-dependent cardiomyocyte atrophy

Area of Science:

• Cardiology
• Molecular Biology
• Cellular Biology

Background:

• Mechanical assist device therapy is a growing treatment for advanced heart failure.
• This therapy can induce reverse remodeling in some patients, but the underlying mechanisms are not fully understood.

Purpose of the Study:

• To investigate the mechanisms by which mechanical unloading affects cardiac muscle.
• To determine the role of the transcription factor FoxO3 in cardiac muscle atrophy.

Main Methods:

• Studied mechanical unloading in a left ventricular model.
• Engineered transgenic mice with a constitutively active FoxO3 mutant in cardiomyocytes.
• Utilized Bnip3-null mice to assess the role of Bnip3.

Main Results:

• Mechanical unloading activated FoxO3, leading to myocyte atrophy, autophagy, and decreased mitochondrial function.
• Constitutively active FoxO3 in mice caused cardiac atrophy, autophagy, and early mortality.
• Bnip3 deficiency partially blunted atrophy and autophagy but not mortality; proteasome inhibitors attenuated cardiac dysfunction.

Conclusions:

• FoxO3, activated by mechanical unloading, is a master regulator of cardiac muscle atrophy.
• FoxO3 controls both autophagy-lysosomal and ubiquitin-proteasomal pathways in the heart.
• Understanding FoxO3's role is crucial for developing therapies for heart failure.