Control of cytokinesis by β-adrenergic receptors indicates an approach for regulating cardiomyocyte endowment

Area of Science:

• Cardiology
• Molecular Biology
• Developmental Biology

Background:

• Congenital heart disease (CHD) affects one million US patients, posing lifelong heart failure risks.
• Existing research inadequately explains heart failure mechanisms specific to CHD populations.

Purpose of the Study:

• To investigate the mechanisms of heart failure development in congenital heart disease.
• To identify therapeutic targets for improving cardiomyocyte endowment and function in CHD.

Main Methods:

• Analysis of heart tissue from an infant with tetralogy of Fallot with pulmonary stenosis (ToF/PS) using isotope-tagged thymidine.
• Single-cell transcriptional profiling to identify key genes involved in cardiomyocyte division.
• Inactivation of beta-adrenergic receptor (β-AR) genes and propranolol administration in neonatal mice models.
• In vitro studies on ToF/PS cardiomyocytes.

Main Results:

• Increased cardiomyocyte cytokinesis failure was observed in ToF/PS.
• Repression of the ECT2 gene, downstream of β-ARs, was identified as the mechanism for cytokinesis failure.
• β-AR gene inactivation and propranolol treatment enhanced cardiomyocyte division in neonatal mice, increasing cardiomyocyte endowment.
• Propranolol treatment improved outcomes after myocardial infarction in adult mice and enabled ToF/PS cardiomyocyte division in vitro.

Conclusions:

• Findings suggest that targeting β-AR signaling can promote cardiomyocyte division.
• Beta-blockers like propranolol show potential for therapeutic evaluation in ToF/PS and other CHD patients to increase cardiomyocyte numbers.