HMGB2 Promotes Cardiomyocyte Proliferation and Heart Regeneration Through MTA2-Driven Metabolic Reprogramming.

Area of Science:

• Cardiovascular Biology
• Regenerative Medicine
• Molecular Cardiology

Background:

• Neonatal hearts exhibit remarkable regenerative capacity post-injury.
• Understanding regeneration mechanisms is key for developing new cardiac therapies.
• Cardiomyocyte proliferation is essential for heart repair, but declines with age.

Purpose of the Study:

• Identify key regulators of cardiomyocyte proliferation and heart regeneration.
• Investigate the role of high mobility group box 2 (HMGB2) in cardiac repair.
• Elucidate the molecular pathways by which HMGB2 promotes regeneration.

Main Methods:

• Quantitative proteomics with tandem mass tag labeling.
• RNA-sequencing (RNA-seq) and single-nucleus RNA-seq.
• In vivo mouse models with genetic manipulation (knockdown/overexpression) and surgical injury (apical resection, myocardial infarction).
• Immunoprecipitation-mass spectrometry (IP-MS) for protein interaction studies.

Main Results:

• HMGB2 identified as a crucial regulator of cardiomyocyte proliferation; its expression decreases with age but is upregulated post-injury.
• HMGB2 knockdown impairs neonatal heart regeneration, while HMGB2 overexpression enhances adult cardiac repair post-myocardial infarction.
• HMGB2 promotes proliferation via the hypoxia-inducible factor 1α (HIF-1α)-mediated glycolysis pathway.
• HMGB2 stabilizes HIF-1α by inhibiting MTA2 ubiquitination and degradation.
• Overexpression of HIF-1α or MTA2 also promotes cardiomyocyte proliferation and cardiac repair.

Conclusions:

• HMGB2 is a critical driver of heart regeneration by regulating cardiomyocyte proliferation and glycolysis.
• The HMGB2-MTA2-HIF-1α axis represents a novel therapeutic target for promoting cardiac repair.
• Targeting this pathway holds potential for regenerative therapies in patients with heart damage.