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Updated: Oct 12, 2025
Simultaneous Assessment of Cardiomyocyte DNA Synthesis and Ploidy: A Method to Assist Quantification of Cardiomyocyte Regeneration and Turnover
Published on: May 23, 2016
Cardiomyocytes disrupt pyrimidine biosynthesis in nonmyocytes to regulate heart repair
Shen Li1,2,3,4,5,6, Tomohiro Yokota1,2,3,4,5,6, Ping Wang1,2,3,4,5,6
1Division of Cardiology, Department of Medicine and.
Insights
Cardiomyocytes regulate heart repair by controlling nucleotide metabolism in nonmuscle cells. Targeting the ENPP1/AMP pathway with inhibitors enhances cardiac repair after injury.
Area of Science:
- Cardiovascular Biology
- Cellular Metabolism
- Regenerative Medicine
Background:
- Cardiac injury recruits various cells, but cardiomyocyte regulation of heart repair remains unclear.
- Understanding cardiomyocyte-mediated signaling is crucial for developing effective cardiac repair strategies.
Purpose of the Study:
- To investigate the role of cardiomyocytes in regulating nonmyocyte behavior after cardiac injury.
- To identify molecular mechanisms by which cardiomyocytes influence heart repair.
- To explore therapeutic targets for enhancing cardiac regeneration.
Main Methods:
- Murine model of ischemic cardiac injury.
- Analysis of ectonucleotidase ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1) expression and activity.
- Assessment of nucleotide metabolism and pyrimidine biosynthesis in nonmyocytes.
- Pharmacological and genetic targeting of the ENPP1/AMP pathway.
- Evaluation of cardiac repair and function post-injury.
Main Results:
- Cardiac injury upregulated ENPP1, leading to ATP hydrolysis and AMP production.
- Cardiomyocytes released adenine and ribonucleosides, disrupting nonmyocyte pyrimidine biosynthesis and inducing cell death.
- Uridine administration or ENPP1/AMP pathway inhibition rescued pyrimidine biosynthesis and enhanced cardiac repair.
- ENPP1 inhibitors improved cardiac repair and postinfarct heart function.
Conclusions:
- Cardiomyocytes actively regulate nonmyocyte pyrimidine metabolism and cell fate after cardiac injury.
- Targeting the ENPP1/AMP pathway offers a promising therapeutic strategy for augmenting cardiac repair.
- Intercellular regulation of pyrimidine biosynthesis is a key mechanism in tissue regeneration.
Abstract:
Various populations of cells are recruited to the heart after cardiac injury, but little is known about whether cardiomyocytes directly regulate heart repair. Using a murine model of ischemic cardiac injury, we demonstrate that cardiomyocytes play a pivotal role in heart repair by regulating nucleotide metabolism and fates of nonmyocytes. Cardiac injury induced the expression of the ectonucleotidase ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1), which hydrolyzes extracellular ATP to form AMP. In response to AMP, cardiomyocytes released adenine and specific ribonucleosides that disrupted pyrimidine biosynthesis at the orotidine monophosphate (OMP) synthesis step and induced genotoxic stress and p53-mediated cell death of cycling nonmyocytes. As nonmyocytes are critical for heart repair, we showed that rescue of pyrimidine biosynthesis by administration of uridine or by genetic targeting of the ENPP1/AMP pathway enhanced repair after cardiac injury. We identified ENPP1 inhibitors using small molecule screening and showed that systemic administration of an ENPP1 inhibitor after heart injury rescued pyrimidine biosynthesis in nonmyocyte cells and augmented cardiac repair and postinfarct heart function. These observations demonstrate that the cardiac muscle cell regulates pyrimidine metabolism in nonmuscle cells by releasing adenine and specific nucleosides after heart injury and provide insight into how intercellular regulation of pyrimidine biosynthesis can be targeted and monitored for augmenting tissue repair.
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