Objectives: Heart failure is the leading cause of death among Americans and contributes to medical costs of up to 31 billion dollars each year in the US. A major cause of systolic heart failure is that adult mammals poorly regenerate injured hearts, the most common being infarction. Previously, we identified that neonatal mice could regenerate their injured hearts. However, this ability is lost seven days after birth. A major event in cardiomyocyte maturation that occurs during the transition from a neonatal to an adult state is a metabolic switch in energy utilization by cardiomyocytes. Embryonic and neonatal cardiomyocytes generate energy through glycolysis, while adult cardiomyocytes generate energy through fatty acid oxidation. Carnitine palmitoyltransferase (CPT)1 is a key enzyme in regulating fatty acid oxidation. Thus, CPT1 could be a key regulator of cardiomyocyte proliferation. However, the role of CPT1 inhibition during heart failure and regeneration in mouse models remains unclear.
Methods: Thus, we hypothesize that CPT1 inhibition will promote heart regeneration. To investigate the role of CPT1 inhibition during heart regeneration, we utilized the neonatal mice at postnatal day 7 (P7) for myocardial infarction (MI) surgery. Mice were then treated with the CPT1 inhibitor, etomoxir, for two weeks after the MI injury. We performed various analyses, including immunohistochemistry for cardiomyocyte proliferation and trichrome staining for heart regeneration.
Results: Our results demonstrate that inhibition of CPT1 by etomoxir injection after MI promotes cardiomyocyte proliferation, as measured by mitosis marker phospho-histone 3 (pH3) and cytokinesis marker Aurora B staining. Remarkably, etomoxir injection to the neonatal mouse heart for two weeks after MI injury reduces scar formation and enhances heart regeneration revealed by trichrome staining.
Conclusions: CPT1 inhibition by etomoxir promotes postnatal cardiomyocyte proliferation and heart regeneration. These findings support a potentially important new therapeutic approach for human heart failure.
Funding Sources: Start-up fund from Oklahoma State University to Jiyoung Bae
