ArticleThe Journal of clinical investigation2022
Cardiomyocytes disrupt pyrimidine biosynthesis in nonmyocytes to regulate heart repair.
Article in The Journal of clinical investigation, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 25 papers.
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25 citing papers in PubMed, 39 citations in OpenAlex.
- Deciphering the role of cell-free extrachromosomal circular DNA in human heart failure.Human genomics · 2026Article
- Cardiac fibroblasts in myocardial injury and heart failure.European heart journal · 2026Review
- A systems genetics approach to uncover mitochondrial drivers of heart failure reveals mitochondria-nuclear cross talk in genetically diverse mouse strains.bioRxiv : the preprint server for biology · 2025Article
- Mapping DNA methylation to cardiac pathologies induced by beta-adrenergic stimulation in a large panel of mice.Epigenetics · 2025Article
- Molecular gatekeepers of endogenous adult mammalian cardiomyocyte proliferation.Nature reviews. Cardiology · 2025Review
- A Distinctive Metabolomics Pattern Associated with the Administration of Combined Sacubitril/Valsartan to Healthy Subjects: A Kinetic Approach.Pharmaceuticals (Basel, Switzerland) · 2025Article
- Integrated transcriptomic analysis unveils molecular mechanisms regulating meat quality in newly improved black goat breeds.NPJ science of food · 2025Article
- Metabolic reaction fluxes as amplifiers and buffers of risk alleles for coronary artery disease.Molecular systems biology · 2025Article
- Genome-wide association study in chondrocalcinosis reveals ENPP1 as a candidate therapeutic target in calcium pyrophosphate deposition disease.Annals of the rheumatic diseases · 2025Article
- Bioinformatics-based Analysis and Verification of Chromatin Regulators and the Mechanism of Immune Infiltration Associated with Myocardial Infarction.Current medicinal chemistry · 2025Article
- Landscape of targets within nucleoside metabolism for the modification of immune responses.Frontiers in oncology · 2025Review
- Role of ENPP1 in cancer pathogenesis: Mechanisms and clinical implications (Review).Oncology letters · 2024Review
- A humanized monoclonal antibody targeting an ectonucleotidase rescues cardiac metabolism and heart function after myocardial infarction.Cell reports. Medicine · 2024Article
- Bone-marrow macrophage-derived GPNMB protein binds to orphan receptor GPR39 and plays a critical role in cardiac repair.Nature cardiovascular research · 2024Article
- Epitranscriptomic regulation of lipid oxidation and liver fibrosis via ENPP1 mRNA mCellular and molecular life sciences : CMLS · 2024Article
- Serine protease inhibitor, SerpinA3n, regulates cardiac remodelling after myocardial infarction.Cardiovascular research · 2024Article
- The Purinergic Nature of Pseudoxanthoma Elasticum.Biology · 2024Review
- Protective Effect of Uridine on Structural and Functional Rearrangements in Heart Mitochondria after a High-Dose Isoprenaline Exposure Modelling Stress-Induced Cardiomyopathy in Rats.International journal of molecular sciences · 2023Article
- Metabolite signaling in the heart.Nature cardiovascular research · 2023Review
- Uridine Inhibits Hepatocellular Carcinoma Cell Development by Inducing Ferroptosis.Journal of clinical medicine · 2023Article
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32 authors at 9 institutions in 4 countries.
Funding
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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