Targeting PFK-2 to promote cardiomyocyte proliferation

The National Institutes of Health National Heart Lung and Blood Institute awarded Oklahoma State University $552,649 on July 1, 2026, under the Cardiovascular Diseases Research program (CFDA 93.837) to investigate the role of phosphofructokinase-2 (PFK-2) in promoting cardiomyocyte proliferation and heart regeneration following myocardial injury.

The research addresses the inability of adult mammalian hearts to regenerate tissue after injury such as heart attack. Unlike neonatal and some non-mammalian vertebrate hearts, adult hearts cannot fully regenerate, a difference the investigator attributes partly to metabolic shifts from glycolysis in regenerative neonatal hearts to oxidative phosphorylation in adult hearts. The project tests whether targeting PFK-2, a regulator of glucose metabolism, can promote heart regeneration by reprogramming cardiac metabolism to mimic the regenerative neonatal metabolic profile. The work includes two aims: investigating the essential role of cardiac-specific PFK-2 in myocardial regeneration to determine whether it is the primary reason for impaired neonatal heart regeneration, and determining the metabolic and molecular mechanisms by which PFK-2 inhibition regulates cardiomyocyte proliferation.

The period of performance runs from July 1, 2026, through June 30, 2029. Work is performed in Stillwater, Oklahoma. The assistance type is Project Grant.

Abstract

Heart disease is the leading cause of death and illness in the united states. A major challenge is the inability of adult hearts to regenerate tissue after injuries such as a heart attack. Interestingly, some non-mammalian vertebrates like zebrafish, and even neonatal mice for a brief period after birth, can fully regenerate their hearts after injury. Zebrafish and early neonatal mouse hearts have fewer mitochondria compared to later postnatal and adult mice, leading to a metabolic shift from glycolysis in embryonic and neonatal cardiomyocytes to oxidative phosphorylation in adult cardiomyocytes. This metabolic shift induces DNA damage and contributes to postnatal cell-cycle exit, highlighting the central role of cardiac metabolism in the regeneration process. Interventions that stimulate glucose metabolism could promote regeneration by mimicking the metabolic profile of a regenerative neonatal heart. Understanding these metabolic pathways is essential for therapeutic development. We recently discovered that 6-phosphofructo-2-kinase/fructose-2,6BISPHOSPHATASE (PFK-2) inhibitor 3PO injection in neonatal mice inhibits cardiomyocyte proliferation and heart regeneration following myocardial infarction (MI). Moreover, global proteomics analysis reveals that 3PO treated PFK-2 inhibition leads to reduced expression of key glycolytic proteins. However, the mechanisms by which cardiac-specific PFK-2 inhibition regulates cardiomyocyte proliferation and heart regeneration remain unclear. We hypothesize that targeting PFK-2, a regulator of glucose metabolism, could impact heart regeneration following injury through a metabolic reprogramming. We propose two aims to test this hypothesis: 1) to investigate the essential role of cardiac-specific PFK-2 in myocardial regeneration and determine if IT is the primary reason for impaired neonatal heart regeneration; 2) to determine the metabolic and molecular mechanisms by which PFK-2 inhibition impedes post-MI regeneration in mammalian hearts. We will use genetic mouse models to specifically inhibit PFK-2 in cardiomyocytes to determine if impaired neonatal heart regeneration is due to cardiac-specific PFK-2 inhibition rather than indirect effects on the heart. The outcome of this study will provide mechanistic insights into heart regeneration following MI and contribute to the development of strategies to prevent heart failure. In line with the NIH academic research enhancement award (R15 area) program, this study will support undergraduate and graduate students by providing research training and educational opportunities in heart failure and cardiac regeneration research.