Cardiomyocytes disrupt pyrimidine biosynthesis in nonmyocytes to regulate heart repair
Shen Li, … , Caius G. Radu, Arjun Deb
Shen Li, … , Caius G. Radu, Arjun Deb
Published November 23, 2021
Citation Information: J Clin Invest. 2022;132(2):e149711. https://doi.org/10.1172/JCI149711.
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Research Article Cardiology

Cardiomyocytes disrupt pyrimidine biosynthesis in nonmyocytes to regulate heart repair

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.

Authors

Shen Li, Tomohiro Yokota, Ping Wang, Johanna ten Hoeve, Feiyang Ma, Thuc M. Le, Evan R. Abt, Yonggang Zhou, Rimao Wu, Maxine Nanthavongdouangsy, Abraham Rodriguez, Yijie Wang, Yen-Ju Lin, Hayato Muranaka, Mark Sharpley, Demetrios T. Braddock, Vicky E. MacRae, Utpal Banerjee, Pei-Yu Chiou, Marcus Seldin, Dian Huang, Michael Teitell, Ilya Gertsman, Michael Jung, Steven J. Bensinger, Robert Damoiseaux, Kym Faull, Matteo Pellegrini, Aldons J. Lusis, Thomas G. Graeber, Caius G. Radu, Arjun Deb

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Figure 5

Single-cell RNA-Seq of nonmyocytes in control and ENPP1CKO animals at 7 days following cardiac injury.

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Single-cell RNA-Seq of nonmyocytes in control and ENPP1CKO animals at 7 ...
(A) Uniform manifold approximation and projection (UMAP) demonstrating different phenotypes of nonmyocyte cell clusters in the injured heart and (B) distribution of WT and ENPP1CKO cells across these clusters. (C) Fraction of endothelial cell, fibroblasts, and macrophages at 7 days following injury. Violin plot demonstrating (D) ENPP1 expression (**P = 5.29 × 10–132) and (E) UMAP demonstrating significantly reduced distribution of Acta2 (myofibroblast marker) in CFs of ENPP1CKO versus control animals and (F) quantitation (%) of myofibroblasts. (G) Violin plot demonstrating decreased expression of other myofibroblast genes Cnn2 (**P = 3.63 × 10–24) and Tagln (***P = 5.40 × 10–17) in ENPP1CKO fibroblasts. (H) Immunostaining for myofibroblasts (αSMA expression, arrowheads) in ENPP1CKO and WT animals and (I) quantitation of myofibroblast numbers. Data are represented as mean ± SEM. n = 5. **P < 0.01, 2-tailed Student’s t test. Scale bar: 10 μm.