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 10

Pyrimidine supplementation with systemic uridine administration is associated with significantly better cardiac repair and postinjury heart function.

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Pyrimidine supplementation with systemic uridine administration is assoc...
(A) Schematic of continuous uridine administration by a subcutaneous pump starting 1 day prior to injury and continuing for 14 days after. (B) B and M mode echocardiogram demonstrating better preservation of contractile function during diastole (green arrows) and systole (yellow arrows) in uridine-injected animals. (C) EF and fractional shortening and LV internal diameter in systole and diastole following uridine administration. n = 15 (vehicle) and n = 15 (uridine) at basal, 1 week, 2 weeks, and 3 weeks; n = 14 (vehicle) and n = 15 (uridine) at 4 weeks. (D) Pie chart demonstrating fraction of animals with mild, moderate, and severe reductions in EF following vehicle or uridine administration. (E) Masson trichrome staining demonstrating scar size (blue) at apex and midventricles of vehicle- or uridine-injected animals and (F) quantitation of differences in scar size as a fraction of the LV surface area. n = 14 (vehicle) and 15 (uridine). Scale bar: 1 mm. (G) Pie chart demonstrating fraction of animals demonstrating mild, moderate, and severe fibrosis following vehicle or uridine administration, (H) Heart weight, body weight, and HW/BW ratio in vehicle- versus uridine-treated animals. n = 14 (vehicle) and n = 15 (uridine). (I) Histology demonstrating capillaries (CD31 staining) in injured regions of hearts 4 weeks after injury in vehicle- or uridine-treated animals and (J) quantitation of capillaries. n = 14 (vehicle) and 15 (uridine). Scale bar: 10 μm. Data are represented as mean ± SEM. **P < 0.01, ordinary 2-way ANOVA with Šidák’s multiple comparisons test (C) or 2-tailed Student’s t test (F, H, and J).