Cardiomyocyte Foxp1-Specific Deletion Promotes Post-injury Heart Regeneration via Targeting Usp20-HIF1ɑ-Hand1...

Area of Science:

• Cardiovascular Biology
• Regenerative Medicine
• Molecular Cardiology

Background:

• The adult mammalian heart exhibits limited capacity for tissue repair post-injury.
• Forkhead box P1 (Foxp1) is crucial for embryonic heart development but its role in postnatal regeneration is unknown.

Purpose of the Study:

• To investigate the role of Foxp1 in cardiomyocyte proliferation and heart regeneration after injury.
• To elucidate the molecular mechanisms by which Foxp1 influences cardiac repair.

Main Methods:

• Analysis of Foxp1 expression in cardiomyocytes following neonatal and adult heart injury models.
• Utilizing single-cell transcriptome databases to assess Foxp1 levels in regenerative cardiomyocyte populations.
• Employing loss-of-function and gain-of-function studies of Foxp1 in cardiomyocytes.
• Investigating the regulatory pathway involving USP20, HIF1α, and Hand1.
• Using AAV9-mediated Hand1 induction in cardiomyocytes for therapeutic assessment.

Main Results:

• Foxp1 expression is downregulated in border zone cardiomyocytes after injury.
• Reduced Foxp1 correlates with higher regenerative potential in cardiomyocytes.
• Loss of Foxp1 enhances cardiomyocyte proliferation, while its gain-of-function suppresses it.
• Foxp1 regulates HIF1α and Hand1, promoting a metabolic shift towards glycolysis.
• AAV9-mediated Hand1 induction improved cardiac regeneration and function.

Conclusions:

• Foxp1 acts as a suppressor of cardiomyocyte proliferation and heart regeneration.
• The Foxp1-USP20-HIF1α-Hand1 pathway is a key regulator of cardiac repair.
• Targeting Hand1 offers a promising therapeutic avenue for heart failure treatment.